Pyrimidine derivatives for the treatment of abnormal cell growth

ABSTRACT

The present invention relates to a compound of the formula 1 
     
       
         
         
             
             
         
       
         
         
           
             or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein R 1 –R 4  and Ar are as defined herein. Such novel pyrimidine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.

CROSS-REFERENCE TO RELATED APPLICATION(S)

Reference is made to U.S. Application Ser. No. 60/571,197, filed May 14,2004, the disclosure of which is incorporated herein by reference in itsentirety.

BACKGROUND OF THE INVENTION

This invention relates to novel pyrimidine derivatives that are usefulin the treatment of abnormal cell growth, such as cancer, in mammals.This invention also relates to a method of using such compounds in thetreatment of abnormal cell growth in mammals, especially humans, and topharmaceutical compositions containing such compounds.

It is known that a cell may become cancerous by virtue of thetransformation of a portion of its DNA into an oncogene (i.e., a genewhich, on activation, leads to the formation of malignant tumor cells).Many oncogenes encode proteins that are aberrant tyrosine kinasescapable of causing cell transformation. Alternatively, theoverexpression of a normal proto-oncogenic tyrosine kinase may alsoresult in proliferative disorders, sometimes resulting in a malignantphenotype.

Receptor tyrosine kinases are enzymes which span the cell membrane andpossess an extracellular binding domain for growth factors such asepidermal growth factor, a transmembrane domain, and an intracellularportion which functions as a kinase to phosphorylate specific tyrosineresidues in proteins and hence to influence cell proliferation. Otherreceptor tyrosine kinases include c-erbB-2, c-met, tie-2, PDGFr, FGFr,and VEGFR. It is known that such kinases are frequently aberrantlyexpressed in common human cancers such as breast cancer,gastrointestinal cancer such as colon, rectal or stomach cancer,leukemia, and ovarian, bronchial or pancreatic cancer. It has also beenshown that epidermal growth factor receptor (EGFR), which possessestyrosine kinase activity, is mutated and/or overexpressed in many humancancers such as brain, lung, squamous cell, bladder, gastric, breast,head and neck, oesophageal, gynecological and thyroid tumors.

Accordingly, it has been recognized that inhibitors of receptor tyrosinekinases are useful as selective inhibitors of the growth of mammaliancancer cells. For example, erbstatin, a tyrosine kinase inhibitor,selectively attenuates the growth in athymic nude mice of a transplantedhuman mammary carcinoma that expresses epidermal growth factor receptortyrosine kinase (EGFR) but is without effect on the growth of anothercarcinoma that does not express the EGF receptor. Thus, selectiveinhibitors of certain receptor tyrosine kinases, are useful in thetreatment of abnormal cell growth, in particular cancer, in mammals. Inaddition to receptor tyrosine kinses, selective inhibitors of certainnon-receptor tyrosine kinases, such as FAK (focal adhesion kinase), lck,src, abl or serine/threonine kinases (e.g., cyclin dependent kinases),are useful in the treatment of abnormal cell growth, in particularcancer, in mammals. FAK is also known as the Protein-Tyrosine Kinase 2,PTK2.

Convincing evidence suggests that FAK, a cytoplasmic, non-receptortyrosine kinase, plays an essential role in cell-matrix signaltransduction pathways (Clark and Brugge 1995, Science 268: 233–239) andits aberrant activation is associated with an increase in the metastaticpotential of tumors (Owens et al. 1995, Cancer Research 55: 2752–2755).FAK was originally identified as a 125 kDa protein highlytyrosine-phosphorylated in cells transformed by v-Src. FAK wassubsequently found to be a tyrosine kinase that localizes to focaladhesions, which are contact points between cultured cells and theirunderlying substratum and sites of intense tyrosine phosphorylation. FAKis phosphorylated and, thus, activated in response to extracellularmatrix (ECM)-binding to integrins. Recently, studies have demonstratedthat an increase in FAK mRNA levels accompanied invasive transformationof tumors and attenuation of the expression of FAK (through the use ofantisense oligonucleotides) induces apoptosis in tumor cells (Xu et al.1996, Cell Growth and Diff. 7: 413–418). In addition to being expressedin most tissue types, FAK is found at elevated levels in most humancancers, particularly in highly invasive metastases.

Various compounds, such as styrene derivatives, have also been shown topossess tyrosine kinase inhibitory properties. Five European patentpublications, namely EP 0 566 226 A1 (published Oct. 20, 1993), EP 0 602851 A1 (published Jun. 22, 1994), EP 0 635 507 A1 (published Jan. 25,1995), EP 0 635 498 A1 (published Jan. 25, 1995), and EP 0 520 722 A1(published Dec. 30, 1992), refer to certain bicyclic derivatives, inparticular quinazoline derivatives, as possessing anti-cancer propertiesthat result from their tyrosine kinase inhibitory properties.

Also, World Patent Application WO 92/20642 (published Nov. 26, 1992),refers to certain bis-mono and bicyclic aryl and heteroaryl compounds astyrosine kinase inhibitors that are useful in inhibiting abnormal cellproliferation. World Patent Applications WO96/16960 (published Jun. 6,1996), WO 96/09294 (published Mar. 6, 1996), WO 97/30034 (published Aug.21, 1997), WO 98/02434 (published Jan. 22, 1998), WO 98/02437 (publishedJan. 22, 1998), and WO 98/02438 (published Jan. 22, 1998), also refer tosubstituted bicyclic heteroaromatic derivatives as tyrosine kinaseinhibitors that are useful for the same purpose. In addition, thefollowing list of publications relate to bis-mono and bicyclic aryl andheteroaryl compounds that may optionally be used as tyrosine kinaseinhibitors: WO 03/030909, WO 03/032997, US Patent Application No.2003/0181474, US Patent Application No. 2003/0162802, U.S. Pat. No.5,863,924, WO 03/078404, U.S. Pat. No. 4,507,146, WO 99/41253, WO01/72744, WO 02/48133, US Patent Application No. 2002/156087, WO02/102783, and WO 03/063794.

U.S. patent application Ser. No. 10/734,039, filed Dec. 11, 2003 relatesto a broad class of novel pyrimidine derivatives that are kinaseinhibitors, and more specifically, inhibitors of FAK. Moreover, U.S.patent application Ser. No. 10/733,215, filed Dec. 11, 2003 relate morespecifically a subset of pyrimidine derivatives, i.e., those bearing a5-aminooxindole, which are tyrosine kinase inhibitors, and moreparticularly, FAK inhibitors. Compounds such as these are useful in thetreatment of abnormal cell growth.

Accordingly, a need exists for additional selective inhibitors ofcertain receptor and non-receptor tyrosine kinases, useful in thetreatment of abnormal cell growth, such as cancer, in mammals. Thepresent invention provides novel pyrimidine derivatives that are kinaseinhibitors and inhibitors of the non-receptor tyrosine kinase, FAK, andare useful in the treatment of abnormal cell growth.

SUMMARY OF THE INVENTION

Thus, the invention provides a compound of the formula 1

or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof,

wherein Ar is selected from:

and ring B is

wherein m is an integer from 0 to 2,

Ra is a substituent attached to any aromatic carbon capable ofsubstitution, wherein Ra is selected from the group consisting ofhydrogen, halogen, hydroxy, —CF₃, —CN, —(C₁–C₆)alkyl, —NR⁵R⁶, —OR¹²,—(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —CO₂R¹², —CONR⁵R⁶ and—CONR⁵R⁸;

Rb is a substituent selected from the group consisting of hydrogen,—(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —CO₂R¹², and—CONR⁵R⁶;

each Rc independently represents a substituent selected from the groupconsisting of hydrogen, halogen, hydroxy, —CF₃, —CN, —(C₁–C₆)alkyl,—NR⁵R⁶, —OR¹², —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —CO₂R¹²,—CONR⁵R⁶ and —CONR⁵R⁸;

or two Rc substituents may be taken together with the carbon atom towhich they are attached to form a cyclic group selected from the groupconsisting of —(C₃–C₁₀)-cycloalkyl and —(C₂–C₉)-heterocyclyl;

with the proviso that Ar cannot be

wherein n is an integer from 1 to 3;

each R¹ is a substituent independently selected from the groupconsisting of hydrogen, hydroxy, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —O(C₁–C₆)alkyl, —O(C₃–C₇)cycloalkyl,—O(C₂–C₉)heterocyclyl, —NR⁵R⁶, —SR⁷, —SOR⁷, —SO₂R⁷, —CO₂R¹², —CONR⁵R⁶,—SO₂NR⁵R⁶, —NHCOR¹², —NR¹²CONR⁵R⁶, and —NR¹²SO₂R⁷; wherein said R¹substituents, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl,—O(C₁–C₆)alkyl, —O(C₃–C₇)cycloalkyl, —O(C₂–C₉)heterocyclyl, —NR⁵R⁶,—SR⁷, —SOR⁷, —SO₂R⁷, —CO₂R⁷, —CONR⁵R⁶, —SO₂NR⁵R⁶, —NHCOR¹²,—NR¹²CONR⁵R⁶, and —NR¹²SO₂R⁷, are optionally substituted by one threemoieties independently selected from the group consisting of hydrogen,halogen, hydroxy, —CF₃, —CN, —(C₁–C₆)alkyl, —NR⁵R⁶, —OR¹²,—(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —CO₂R¹², —CONR⁵R⁶ and—CONR⁵R⁸;

each R² is a substituent independently selected from the groupconsisting of hydrogen, —(C₁–C₆)alkyl, —(C₂–C₆)alkenyl, —(C₂–C₆)alkynyl,—(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —CO₂R¹², and —CONR⁵R⁶; whereinsaid R² substituents, —(C₁–C₆)alkyl, —(C₂–C₆)alkenyl, —(C₂–C₆)alkynyl,—(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —CO₂R¹², and —CONR⁵R⁶, areoptionally substituted by one to three moieties independently selectedfrom the group consisting of hydrogen, halogen, hydroxy, —CF₃, —NO₂,—CN, —(C₁–C₆)alkyl, —(C₂–C₆)alkenyl, —(C₂–C₆)alkynyl, —C═N—OH,—C═N—O((C₁–C₆)alkyl), —NR⁵R⁶, —OR¹², —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —CO₂R¹², —CONR⁵R⁶, —CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁵R⁶, —NHCOR¹², —NR¹²CONR⁵R⁶, and —NR¹²SO₂R⁷, wherein said—(C₂–C₆)alkenyl and —(C₂–C₆)alkynyl R² moieties may be optionallysubstituted by one to three R¹² groups;

R¹ and R² may be taken together with the atom(s) to which they areattached to form a cyclic group, —(C₃–C₁₀)cycloalkyl or—(C₂–C₉)heterocyclyl, wherein said cyclic group is optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CF₃, —NO₂, —CN,—(C₁–C₆)alkyl, —(C₂–C₆)alkenyl, —(C₂–C₆)alkynyl, —C═N—OH,—C═N—O((C₁–C₆)alkyl), —NR⁵R⁶, —OR¹², —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —CO₂R¹², —CONR⁵R⁶, —CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁵R⁵R⁶, —NHCOR¹², —NR¹²CONR⁵R⁶, and —NR¹²SO₂R⁷, wherein said—(C₂–C₆)alkenyl and —(C₂–C₆)alkynyl moieties of said cyclic group may beoptionally substituted by one to three R¹² groups, and said cyclic groupis optionally interrupted by one to three elements selected from thegroup consisting of —(C═O), —SO₂, —S—, —O—, —N—, —NH— and —NR¹²;

R³ is a substituent selected from the group consisting of:

-   -   (a) hydrogen;    -   (b) —(C₆–C₁₀)aryl or —(C₁–C₉)heteroaryl, optionally substituted        by one to three moieties independently selected from the group        consisting of halogen, hydroxy, —(C₁–C₆)alkyl,        —(C₁–C₆)alkyl-P(O)(O(C₁–C₆)alkyl)₂, —(C₃–C₁₀)cycloalkyl,        (C₆–C₁₀)aryl, (C₂–C₉)heterocyclyl, —(C₁–C₉)heteroaryl, —NR⁵R⁶,        —NHSO₂(C₁–C₆)alkyl, —NHSO₂(C₃–C₆)cycloalkyl,        —N((C₁–C₆)alkyl)(SO₂—C₁–C₆)alkyl),        —N((C₁–C₆)alkyl)(SO₂(C₃–C₆)cycloalkyl),        —N((C₃–C₆)cycloalkyl)(SO₂—C₁–C₆)alkyl),        —N((C₃–C₆)cycloalkyl)(SO₂(C₃–C₆)cycloalkyl), —O(C₁–C₆)alkyl,        —O—SO₂(C₁–C₆)alkyl, —O—SO₂(C₃–C₆)cycloalkyl, —(CO)(C₁–C₆)alkyl,        —(CO)CF₃, —(CO)(C₃–C₁₀)cycloalkyl, —(CO)(C₆–C₁₀)aryl,        —(CO)(C₂–C₉)heterocyclyl, —(CO)(C₁–C₉)heteroaryl,        —(CO)O(C₁–C₆)alkyl, —(CO)O(C₃–C₁₀)cycloalkyl,        —(CO)O(C₆–C₁₀)aryl, —(CO)O(C₂–C₉)heterocyclyl,        —(CO)O(C₁–C₉)heteroaryl, —(CO)(C₁–C₆)alkyl-O(C₁–C₆)alkyl,        —SO₂(C₁–C₆)alkyl, —SO₂(C₃–C₆)cycloalkyl, SO₂CF₃, SO₂NH₂,        SO₂NH(C₁–C₆)alkyl, —SO₂NH(C₃–C₆)cycloalkyl,        —SO₂N((C₁–C₆)alkyl)₂, SO₂N((C₁–C₆)alkyl)((C₃–C₆)cycloalkyl),        —SO₂N((C₃–C₆)cycloalkyl)₂ and —SO₂NR⁵R⁶, wherein said —(C₆–C₁₀)        aryl or —(C₁–C₉) heteroaryl are optionally interrupted by one to        three elements selected from the group consisting of —S—, —O—,        —N—, —NH— and —NR¹²;    -   (c) —(C₃–C₁₀)cycloalkyl, —(C₂–C₉)heterocyclyl, and        —(C₁–C₆)alkyl-(C₂–C₉) heterocyclyl, optionally substituted by        one to three moieties independently selected from the group        consisting of halogen, hydroxy, —(C₁–C₆)alkyl,        —(C₁–C₆)alkyl-P(O)(O(C₁–C₆)alkyl)₂, —(C₃–C₁₀)cycloalkyl,        (C₆–C₁₀)aryl, (C₂–C₉)heterocyclyl, —(C₁–C₉)heteroaryl, —NR⁵R⁶,        —NSO₂(C₁–C₆)alkyl, —NHSO₂(C₃–C₆)cycloalkyl,        —N((C₁–C₆)alkyl)(SO₂—C₁–C₆)alkyl),        —N((C₁–C₆)alkyl)(SO₂(C₃–C₆)cycloalkyl),        —N((C₃–C₆)cycloalkyl)(SO₂—C₁–C₆)alkyl),        —N((C₃–C₆)cycloalkyl)(SO₂(C₃–C₆)cycloalkyl), —O(C₁–C₆)alkyl,        —O—SO₂(C₁–C₆)alkyl, —O—SO₂(C₁–C₆)alkyl, —O—SO₂(C₃–C₆)cycloalkyl,        —(CO)(C₁–C₆)alkyl, —(CO)CF₃, —(CO)(C₃–C₁₀)cycloalkyl,        —(CO)(C₆–C₁₀)aryl, —(CO)(C₂–C₉)heterocyclyl,        —(CO)(C₁–C₉)heteroaryl, —(CO)O(C₁–C₆)alkyl,        —(CO)O(C₃–C₁₀)cycloalkyl, —(CO)O(C₆–C₁₀)aryl,        —(CO)O(C₂–C₉)heterocyclyl, —(CO)O(C₁–C₉)heteroaryl,        —(CO)(C₁–C₆)alkyl-O(C₁–C₆)alkyl, —SO₂(C₁–C₆)alkyl,        —SO₂(C₃–C₆)cycloalkyl, SO₂CF₃, SO₂NH₂, SO₂NH(C₁–C₆)alkyl,        —SO₂NH(C₃–C₆)cycloalkyl, —SO₂N((C₁–C₆)alkyl)₂,        SO₂N((C₁–C₆)alkyl)((C₃–C₆)cycloalkyl), —SO₂N((C₃–C₆)cycloalkyl)₂        and —SO₂NR⁵R⁶; wherein said —(C₃–C₁₀)cycloalkyl,        —(C₂–C₉)heterocyclyl, and —(C₁–C₆)alkyl-(C₂–C₉) heterocyclyl are        optionally interrupted by one to three elements selected from        the group consisting of —(C═O), —SO₂, —S—, —O—, —N—, —NH— and        —NR¹²;    -   (d) —(C₁–C₆)alkyl optionally substituted by one to three        moieties selected from the group consisting of halogen, hydroxy,        —(C₁–C₆)alkyl, —(C₁–C₆)alkyl-P(O)(O(C₁–C₆)alkyl)₂,        —(C₃–C₁₀)cycloalkyl, (C₆–C₁₀)aryl, (C₂–C₉)heterocyclyl,        —(C₁–C₉)heteroaryl, —NR⁵R⁶, —NHSO₂(C₁–C₆)alkyl,        —NHSO₂(C₃–C₆)cycloalkyl, —N((C₁–C₆)alkyl)(SO₂—C₁–C₆)alkyl),        —N((C₁–C₆)alkyl)(SO₂(C₃–C₆)cycloalkyl),        —N((C₃–C₆)cycloalkyl)(SO₂—C₁–C₆)alkyl),        —N((C₃–C₆)cycloalkyl)(SO₂(C₃–C₆)cycloalkyl), —O(C₁–C₆)alkyl,        —O—SO₂(C₁–C₆)alkyl, —O—SO₂(C₃–C₆)cycloalkyl, —(CO)(C₁–C₆)alkyl,        —(CO)CF₃, —(CO)(C₃–C₁₀)cycloalkyl, —(CO)(C₆–C₁₀)aryl,        —(CO)(C₂–C₉)heterocyclyl, —(CO)(C₁–C₉)heteroaryl,        —(CO)O(C₁–C₆)alkyl, —(CO)O(C₃–C₁₀)cycloalkyl,        —(CO)O(C₆–C₁₀)aryl, —(CO)O(C₂–C₉)heterocyclyl,        —(CO)O(C₁–C₉)heteroaryl, —(CO)(C₁–C₆)alkyl-O(C₁–C₆)alkyl,        —SO₂(C₁–C₆)alkyl, —SO₂(C₃–C₆)cycloalkyl, SO₂CF₃, SO₂NH₂,        SO₂NH(C₁–C₆)alkyl, —SO₂NH(C₃–C₆)cycloalkyl,        —SO₂N((C₁–C₆)alkyl)₂, SO₂N((C₁–C₆)alkyl)((C₃–C₆)cycloalkyl),        —SO₂N((C₃–C₆)cycloalkyl)₂ and —SO₂NR⁵R⁶, wherein said        —(C₁–C₆)alkyl is optionally interrupted by one to three elements        selected from the group consisting of —(C═O), —SO₂, —S—, —O—,        —N—, —NH— and —NR¹²;

and wherein each R³ (b)–(d) substituent, moiety, or element isoptionally substituted by one to three radicals independently selectedfrom the group consisting of hydrogen, halogen, hydroxy, —CF₃, —NO₂,—CN, —(C₁–C₆)alkyl, —(C₂–C₆)alkenyl, —(C₂–C₆)alkynyl,—(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl,—(C₁–C₉)heteroaryl, —O(C₁–C₆)alkyl, —O(C₃–C₇)cycloalkyl,—O(C₂–C₉)heterocyclyl, —C═N—OH, —C═N—O(C₁–C₆ alkyl), —NR⁵R⁶, —SR⁷,—SOR⁷, —SO₂R⁷, —CO₂R¹², —CONR⁵R⁶, —SO₂NR⁵R⁶, —NHCOR⁵, —NR¹²CONR⁵R⁶, and—NR¹²SO₂R⁷; and wherein R⁵ and R⁶ of said —CONR⁵R⁶, —SO₂NR⁵R⁶, and—NR¹²CONR⁵R⁶ groups may be taken together with the atoms to which theyare attached to form a —(C₂–C₉)heterocyclyl;

R⁴ is a substituent selected from the group consisting of hydrogen,(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, and —(C₂–C₉)heterocyclyl; wherein said(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, and —(C₂–C₉)heterocyclyl R⁴substituents are optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxyl, —(C₁–C₆)alkyl, —CN, —NR⁵R⁶, —OR⁵, —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —CO₂R¹², —SO₂NR⁵R⁶, NR¹²SO₂R⁷, —SO₂R⁷ and—CONR⁵R⁸; wherein R⁵ and R⁸ of said —CONR⁵R⁸ group may be taken togetherwith the atoms to which they are attached to form a—(C₂–C₉)heterocyclyl;

R⁵ and R⁶ are each substituents independently selected from the groupconsisting of hydrogen, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl, —(C₁–C₉)heteroaryl, COR¹² and—SO₂R¹²; wherein said —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl, —(C₁–C₉)heteroaryl, COR¹² and—SO₂R¹² R⁵ or R⁶ substituents are optionally substituted by one to threemoieties independently selected from the group consisting of hydrogen,halogen, —CF₃, —CN, —(C₁–C₆)alkyl, —NH(C₁–C₆)alkyl,—NH(C₃–C₇)cycloalkyl, —NH(C₂–C₉)heterocyclyl, —NH(C₆–C₁₀)aryl,—NH(C₁–C₉)heteroaryl, —N((C₁–C₆)alkyl)₂, —N((C₃–C₇)cycloalkyl)₂,—N((C₂–C₉)heterocyclyl)₂, —N((C₆–C₁₀)aryl)₂, —N((C₁–C₉)heteroaryl)₂,—O(C₁–C₆)alkyl, —O(C₃–C₇)cycloalkyl, —O(C₂–C₉)heterocyclyl,—O(C₆–C₁₀)aryl, —O(C₁–C₉)heteroaryl, —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —CO₂R⁷, SO₂NR⁵R⁶, NR¹²SO₂R⁷, —SO₂R^(7,)—CONH₂,—CONHR⁷, and —CONR⁷R⁸; wherein R⁷ and R⁸ of said —CONR⁷R⁸ group may betaken together with the nitrogen atom to which they are attached to forma —(C₂–C₉)heterocyclyl;

R⁵ and R⁶ may be taken together with the atom(s) to which they areattached to form a —(C₂–C₉)heterocyclyl, wherein said—(C₂–C₉)heterocyclyl group is optionally substituted by one to threemoieties selected from the group consisting of hydrogen, halogen,hydroxy, —CF₃, —NO₂, —CN, —(C₁–C₆)alkyl, —(C₂–C₆)alkenyl,—(C₂–C₆)alkynyl, —C═N—OH, —C═N—O((C₁–C₆)alkyl), —NR⁷R⁸, —OR¹²,—(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —CO₂R¹², —CONR⁷R⁸, —CONR⁵R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁷R⁸, —NHCOR¹², —NR¹²CONR⁷R⁸, and —NR¹²SO₂R⁷,wherein said —(C₂–C₆)alkenyl and —(C₂–C₆)alkynyl moieties of said—(C₂–C₉)heterocyclyl group may be optionally substituted by one to threeR⁷ groups, and said —(C₂–C₉)heterocyclyl group is optionally interruptedby one to three elements selected from the group consisting of —(C═O),—SO₂, —S—, —O—, —N—, —NH— and —NR¹²;

R⁷ is a substituent selected from the group consisting of —(C₁–C₆)alkyl,—(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl, and —(C₁–C₉)heteroaryl; wherein said —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl, and —(C₁–C₉) heteroaryl R⁷substituents are optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁–C₆)alkyl, —NR¹² ₂, and —O(C₁–C₆)alkyl;

R⁸ is a substituent selected from the group consisting of hydrogen,—(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl,and —(C₁–C₉) heteroaryl; wherein said —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl, and —(C₁–C₉) heteroaryl R⁸ radicalsare optionally substituted by one to three moieties independentlyselected from the group consisting of hydrogen, halogen, hydroxy, —CN,—(C₁–C₆)alkyl, —NH₂, —NHR⁹, —NR⁹ ₂, OR⁹, —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —CO₂R¹⁰, —CONH₂, —CONHR¹⁰, and —CONR¹⁰R¹¹; whereinR¹⁰ and R¹¹ of —CONR¹⁰R¹¹ may be taken together with the nitrogen atomto which they are attached to form a —(C₂–C₉)heterocyclyl;

R⁹ and R¹⁰ are each —(C₁–C₆)alkyl;

R¹¹ is hydrogen or —(C₁–C₆)alkyl; and

R¹² is a substituent selected from the group consisting of hydrogen,—(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl,and —(C₁–C₉)heteroaryl; wherein said —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl, and —(C₁–C₉)heteroaryl R¹²substituent is optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,—CF₃, —CN, —(C₁–C₆)alkyl, —NH(C₁–C₆)alkyl, —NH(C₃–C₇)cycloalkyl,—NH(C₂–C₉)heterocyclyl, —NH(C₆–C₁₀)aryl, —NH(C₁–C₉)heteroaryl,—N((C₁–C₆)alkyl)₂, —N((C₃–C₇)cycloalkyl)₂, —N((C₂–C₉)heterocyclyl)₂,—N((C₆–C₁₀)aryl)₂, —N((C₁–C₉)heteroaryl)₂, —O(C₁–C₆)alkyl,—O(C₃–C₇)cycloalkyl, —O(C₂–C₉)heterocyclyl, —O(C₆–C₁₀)aryl,—O(C₁–C₉)heteroaryl, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —CO₂R⁷,—CONH₂, —CONHR⁷, and —CONR⁷R⁸; wherein R⁷ and R⁸ of said —CONR⁷R⁸ groupmay be taken together with the atoms which they are attached to form a—(C₂–C₉) heterocyclyl.

The present invention also includes isotopically-labeled compounds,which are identical to those recited in Formula 1, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of thepresent invention, prodrugs thereof, and pharmaceutically acceptablesalts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of this invention. Certain isotopically-labelled compounds ofthe present invention, for example those into which radioactive isotopessuch as ³H and ¹⁴C are incorporated, are useful in drug and/or substratetissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e.,¹⁴C, isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically-labelled compounds of Formula 1 of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily availableisotopically-labelled reagent for a non-isotopically-labelled reagent.

The present invention also relates to the pharmaceutically acceptableacid addition salts of compounds of the formula 1. The acids which areused to prepare the pharmaceutically acceptable acid addition salts ofthe aforementioned base compounds of this invention are those which formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the chloride, bromide, iodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate,citrate, acid citrate, tartrate, bitartrate, succinate, maleate,fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

The invention also relates to base addition salts of formula 1. Thechemical bases that may be used as reagents to prepare pharmaceuticallyacceptable base salts of those compounds of formula 1 that are acidic innature are those that form non-toxic base salts with such compounds.Such non-toxic base salts include, but are not limited to those derivedfrom such pharmacologically acceptable cations such as alkali metalcations (e.g., potassium and sodium) and alkaline earth metal cations(e.g., calcium and magnesium), ammonium or water-soluble amine additionsalts such as N-methylglucamine-(meglumine), and the loweralkanolammonium and other base salts of pharmaceutically acceptableorganic amines.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, unlessotherwise indicated, includes salts of acidic or basic groups which maybe present in the compounds of the present invention. The compounds ofthe present invention that are basic in nature are capable of forming awide variety of salts with various inorganic and organic acids. Theacids that may be used to prepare pharmaceutically acceptable acidaddition salts of such basic compounds of are those that form non-toxicacid addition salts, i.e., salts containing pharmacologically acceptableanions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate,lactate, salicylate, citrate, acid citrate, tartrate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.The compounds of the present invention that include a basic moiety, suchas an amino group, may form pharmaceutically acceptable salts withvarious amino acids, in addition to the acids mentioned above.

This invention also encompasses pharmaceutical compositions containingprodrugs of compounds of the formula 1. Compounds of formula 1 havingfree amino, amido, hydroxy or carboxylic groups can be converted intoprodrugs. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues which are covalently joined through peptide bonds to freeamino, hydroxy or carboxylic acid groups of compounds of formula 1. Theamino acid residues include the 20 naturally occurring amino acidscommonly designated by three letter symbols and also include,4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Prodrugs also include compounds wherein carbonates, carbamates, amidesand alkyl esters that are covalently bonded to the above substituents offormula 1 through the carbonyl carbon prodrug sidechain.

This invention also encompasses compounds of formula 1 containingprotective groups. One skilled in the art will also appreciate thatcompounds of the invention can also be prepared with certain protectinggroups that are useful for purification or storage and can be removedbefore administration to a patient. The protection and deprotection offunctional groups is described in “Protective Groups in OrganicChemistry”, edited by J. W. F. McOmie, Plenum Press (1973) and“Protective Groups in Organic Synthesis”, 3rd edition, T. W. Greene andP. G. M. Wuts, Wiley-Interscience (1999).

The compounds of this invention include all stereoisomers (e.g., cis andtrans isomers) and all optical isomers of compounds of the formula 1(e.g., R and S enantiomers), as well as racemic, diastereomeric andother mixtures of such isomers.

The compounds, salts and prodrugs of the present invention can exist inseveral tautomeric forms, including the enol and imine form, and theketo and enamine form and geometric isomers and mixtures thereof. Allsuch tautomeric forms are included within the scope of the presentinvention. Tautomers exist as mixtures of a tautomeric set in solution.In solid form, usually one tautomer predominates. Even though onetautomer may be described, the present invention includes all tautomersof the present compounds.

The present invention also includes atropisomers of the presentinvention. Atropisomers refer to compounds of formula 1 that can beseparated into rotationally restricted isomers.

The compounds of this invention may contain olefin-like double bonds.When such bonds are present, the compounds of the invention exist as cisand trans configurations and as mixtures thereof.

The term “interrupted by” refers to compounds in which a ring carbonatom is replaced by an element selected from the group consisting of—(C═O), —SO₂, —S—, —O—, —N—, —NH—, and —NR¹². For example, if asubstituent is —(C₆–C₁₀)aryl, such as

the ring may be interrupted or replaced by a nitrogen heteroatom to formthe following ring:

such that a ring carbon is replaced by the heteroatom nitrogen.Compounds of the invention can accommodate up to three such replacementsor interruptions.

The compounds of the invention may contain Ar groups represented by

Compounds represented by this generic formula refer to fused bicyclicring systems wherein the aromatic ring adjacent to ring B bears one ormore nitrogen atoms in the ring. For example, such a structure may referto one or more of the following ring systems:

A “suitable substituent” is intended to mean a chemically andpharmaceutically acceptable functional group i.e., a moiety that doesnot negate the biological activity of the inventive compounds. Suchsuitable substituents may be routinely selected by those skilled in theart. Illustrative examples of suitable substituents include, but are notlimited to halo groups, perfluoroalkyl groups, perfluoroalkoxy groups,alkyl groups, alkenyl groups, alkynyl groups, hydroxy groups, oxogroups, mercapto groups, alkylthio groups, alkoxy groups, aryl orheteroaryl groups, aryloxy or heteroaryloxy groups, aralkyl orheteroaralkyl groups, aralkoxy or heteroaralkoxy groups, HO—(C═O)—groups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups,alkylcarbonyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groupsdialkylamino carbonyl groups, arylcarbonyl groups, aryloxycarbonylgroups, alkylsulfonyl groups, arylsulfonyl groups and the like. Thoseskilled in the art will appreciate that many substituents can besubstituted by additional substituents. Further examples of suitablesubstituents include those recited in the definition of compounds ofFormula 1, including Ra, Rb, Rc, and R¹ through R¹², as definedhereinabove.

As used herein, the term “alkyl,” as well as the alkyl moieties of othergroups referred herein (e.g., alkoxy), may be linear or branched (suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,secondary-butyl, tertiary-butyl); optionally substituted by 1 to 3suitable substituents as defined above such as fluoro, chloro,trifluoromethyl, (C₁–C₆)alkoxy, (C₆–C₁₀)aryloxy, trifluoromethoxy,difluoromethoxy or (C₁–C₆)alkyl. The phrase “each of said alkyl” as usedherein refers to any of the preceding alkyl moieties within a group suchalkoxy, alkenyl or alkylamino. Preferred alkyls include (C₁–C₆)alkyl,more preferred are (C₁–C₄)alkyl, and most preferred are methyl andethyl.

As used herein, the term “cycloalkyl” refers to a mono, bicyclic ortricyclic carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl,cyclohexenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl andbicyclo[5.2.0]nonanyl, etc.); optionally containing 1 or 2 double bondsand optionally substituted by 1 to 3 suitable substituents as definedabove which includes but is not limited to fluoro, chloro,trifluoromethyl, (C₁–C₆)alkoxy, (C₆–C₁₀)aryloxy, trifluoromethoxy,difluoromethoxy or (C₁–C₆)alkyl.

As used herein, the term “halogen” includes fluoro, chloro, bromo oriodo or fluoride, chloride, bromide or iodide.

As used herein, the term “alkenyl” means straight or branched chainunsaturated radicals of 2 to 6 carbon atoms, including, but not limitedto ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like; optionallysubstituted by 1 to 3 suitable substituents as defined above whichincludes but is not limited to fluoro, chloro, trifluoromethyl,(C₁–C₆)alkoxy, (C₆–C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy or(C₁–C₆)alkyl.

As used herein, the term “alkynyl” is used herein to mean straight orbranched hydrocarbon chain radicals having one triple bond including,but not limited to, ethynyl, propynyl, butynyl, and the like; optionallysubstituted by 1 to 3 suitable substituents as defined above whichincludes but is not limited to fluoro, chloro, trifluoromethyl,(C₁–C₆)alkoxy, (C₆–C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy or(C₁–C₆)alkyl.

As used herein, the term “carbonyl” or “(C═O)” (as used in phrases suchas alkylcarbonyl, alkyl-(C═O)— or alkoxycarbonyl) refers to the joinderof the >C═O moiety to a second moiety such as an alkyl or amino group(i.e. an amido group). Alkoxycarbonylamino (i.e. alkoxy(C═O)—NH—) refersto an alkyl carbamate group. The carbonyl group is also equivalentlydefined herein as (C═O). Alkylcarbonylamino refers to groups such asacetamide.

As used herein, the term “aryl” means aromatic radicals which includesbut is not limited to phenyl, naphthyl, tetrahydronaphthyl, indanyl andthe like; optionally substituted by 1 to 3 suitable substituents asdefined above.

As used herein, the term “heteroaryl” refers to an aromatic heterocyclicgroup usually with one heteroatom selected from O, S and N in the ring.In addition to said heteroatom, the aromatic group may optionally haveup to four N atoms in the ring. For example, heteroaryl group includespyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl,imidazolyl, pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl),thiazolyl (e.g., 1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl,triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g.,1,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), quinolyl,isoquinolyl, benzothienyl, benzofuryl, indolyl, and the like; optionallysubstituted by 1 to 3 suitable substituents as defined above whichincludes but is not limited to fluoro, chloro, trifluoromethyl,(C₁–C₆)alkoxy, (C₆–C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy or(C₁–C₆)alkyl.

The term “heterocyclic” as used herein refers to a cyclic groupcontaining 1–9 carbon atoms and 1 to 4 hetero atoms selected from N, O,S(O)_(n) or NR. Examples of such rings include azetidinyl,tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl,piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl,thiomorpholinyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl,morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl,indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl,benzoxazinyl, and the like. Examples of said monocyclic saturated orpartially saturated ring systems are tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl,imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperazin-1-yl,piperazin-2-yl, piperazin-3-yl, 1,3-oxazolidin-3-yl, isothiazolidine,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,thiomorpholin-yl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazin-yl, morpholin-yl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl,1,2,5-oxathiazin-4-yl and the like; optionally containing 1 or 2 doublebonds and optionally substituted by 1 to 3 suitable substituents asdefined above which includes but is not limited to fluoro, chloro,trifluoromethyl, (C₁–C₆)alkoxy, (C₆–C₁₀)aryloxy, trifluoromethoxy,difluoromethoxy or (C₁–C₆)alkyl.

Nitrogen heteroatoms as used herein refers to N═, >N and —NH; wherein—N═ refers to a nitrogen double bond; >N refers to a nitrogen containingtwo bond connections and —N refers to a nitrogen containing one bond.

“Embodiment” as used herein refers to specific groupings of compounds oruses into discrete subgenera. Such subgenera may be cognizable accordingto one particular substituent such as a specific R¹ or R³ group. Othersubgenera are cognizable according to combinations of varioussubstituents, such as all compounds wherein R² is hydrogen and R¹ is(C₁–C₆)alkyl.

Therefore, the invention provides a compound of formula 1 wherein Ar is

Also provided is a compound of formula 1 wherein Ar is a fused ringsystem selected from the group consisting of:

with the proviso that Rb of formula III cannot be hydrogen.

Still further, the invention provides a compound of formula 1 wherein Aris

Moreover, the invention provides a compound of formula 1 wherein Ar is

with the proviso that Rb is not hydrogen.

A further embodiment of the invention is a compound of formula 1 whereinAr is

Still further, an embodiment of the invention is a compound of formula 1wherein Ar is

Another embodiment of the invention a compound of formula 1 wherein Aris

Also provided is a compound of formula 1 wherein Ar is a heterocyclicfused ring system selected from:

Another embodiment of the invention a compound of formula 1 wherein R³is hydrogen.

A further embodiment of the invention is a compound of formula 1 whereinR³ is selected from the group consisting of —(C₆–C₁₀)aryl and—(C₁–C₉)heteroaryl, optionally substituted by one to three moietiesindependently selected from the group consisting of halogen, hydroxy,—(C₁–C₆)alkyl, —(C₁–C₆)alkyl-P(O)(O(C₁–C₆)alkyl)₂, —(C₃–C₁₀)cycloalkyl,(C₆–C₁₀)aryl, (C₂–C₉)heterocyclyl, —(C₁–C₉)heteroaryl, —NR⁵R⁶,—NHSO₂(C₁–C₆)alkyl, —NHSO₂(C₃–C₆)cycloalkyl,—N((C₁–C₆)alkyl)(SO₂—C₁–C₆)alkyl),—N((C₁–C₆)alkyl)(SO₂(C₃–C₆)cycloalkyl),—N((C₃–C₆)cycloalkyl)(SO₂—C₁–C₆)alkyl),—N((C₃–C₆)cycloalkyl)(SO₂(C₃–C₆)cycloalkyl), —O(C₁–C₆)alkyl,—O—SO₂(C₁–C₆)alkyl, —O—SO₂(C₃–C₆)cycloalkyl, —(CO)(C₁–C₆)alkyl,—(CO)CF₃, —(CO)(C₃–C₁₀)cycloalkyl, —(CO)(C₆–C₁₀)aryl,—(CO)(C₂–C₉)heterocyclyl, —(CO)(C₁–C₉)heteroaryl, —(CO)O(C₁–C₆)alkyl,—(CO)O(C₃–C₁₀)cycloalkyl, —(CO)O(C₆–C₁₀)aryl, —(CO)O(C₂–C₉)heterocyclyl,—(CO)O(C₁–C₉)heteroaryl, —(CO)(C₁–C₆)alkyl-O(C₁–C₆)alkyl,—SO₂(C₁–C₆)alkyl, —SO₂(C₃–C₆)cycloalkyl, SO₂CF₃, SO₂NH₂,SO₂NH(C₁–C₆)alkyl, —SO₂NH(C₃–C₆)cycloalkyl, —SO₂N((C₁–C₆)alkyl)₂,SO₂N((C₁–C₆)alkyl)((C₃–C₆)cycloalkyl), —SO₂N((C₃–C₆)cycloalkyl)₂ and—SO₂NR⁵R⁶, wherein said —(C₆–C₁₀) aryl or —(C₁–C₉) heteroaryl areoptionally interrupted by one to three elements selected from the groupconsisting of —S—, —O—, —N—, —NH— and —NR¹².

Another embodiment of the present invention is a compound of formula 1wherein R³ is selected from the group consisting of —(C₃–C₁₀)cycloalkyl,—(C₂–C₉)heterocyclyl, and —(C₁–C₆)alkyl-(C₂–C₉) heterocyclyl, optionallysubstituted by one to three moieties independently selected from thegroup consisting of halogen, hydroxy, —(C₁–C₆)alkyl,—(C₁–C₆)alkyl-P(O)(O(C₁–C₆)alkyl)₂, —(C₃–C₁₀)cycloalkyl, (C₆–C₁₀)aryl,(C₂–C₉)heterocyclyl, —(C₁–C₉)heteroaryl, —NR⁵R⁶, —NSO₂(C₁–C₆)alkyl,—NHSO₂(C₃–C₆)cycloalkyl, —N((C₁–C₆)alkyl)(SO₂—C₁–C₆)alkyl),—N((C₁–C₆)alkyl)(SO₂(C₃–C₆)cycloalkyl),—N((C₃–C₆)cycloalkyl)(SO₂—C₁–C₆)alkyl),—N((C₃–C₆)cycloalkyl)(SO₂(C₃–C₆)cycloalkyl), —O(C₁–C₆)alkyl,—O—SO₂(C₁–C₆)alkyl, —O—SO₂(C₁–C₆)alkyl, —O—SO₂(C₃–C₆)cycloalkyl,—(CO)(C₁–C₆)alkyl, —(CO)CF₃, —(CO)(C₃–C₁₀)cycloalkyl, —(CO)(C₆–C₁₀)aryl,—(CO)(C₂–C₉)heterocyclyl, —(CO)(C₁–C₉)heteroaryl, —(CO)O(C₁–C₆)alkyl,—(CO)O(C₃–C₁₀)cycloalkyl, —(CO)O(C₆–C₁₀)aryl, —(CO)O(C₂–C₉)heterocyclyl,—(CO)O(C₁–C₉)heteroaryl, —(CO)(C₁–C₆)alkyl-O(C₁–C₆)alkyl,—SO₂(C₁–C₆)alkyl, —SO₂(C₃–C₆)cycloalkyl, SO₂CF₃, SO₂NH₂,SO₂NH(C₁–C₆)alkyl, —SO₂NH(C₃–C₆)cycloalkyl, —SO₂N((C₁–C₆)alkyl)₂,SO₂N((C₁–C₆)alkyl)((C₃–C₆)cycloalkyl), —SO₂N((C₃–C₆)cycloalkyl)₂ and—SO₂NR⁵R⁶, wherein said —(C₃–C₁₀)cycloalkyl, —(C₂–C₉)heterocyclyl, and—(C₁–C₆)alkyl-(C₂–C₉) heterocyclyl are optionally interrupted by one tothree elements selected from the group consisting of —(C═O), —SO₂, —S—,—O—, —N—, —NH— and —NR¹².

A further embodiment of the invention is a compound of formula 1 whereinR³ is —(C₁–C₆)alkyl optionally substituted by one to three moietiesselected from the group consisting of halogen, hydroxy, —(C₁–C₆)alkyl,—(C₁–C₆)alkyl-P(O)(O(C₁–C₆)alkyl)₂, —(C₃–C₁₀)cycloalkyl, (C₆–C₁₀)aryl,(C₂–C₉)heterocyclyl, —(C₁–C₉)heteroaryl, —NR⁵R⁶, —NHSO₂(C₁–C₆)alkyl,—NHSO₂(C₃–C₆)cycloalkyl, —N((C₁–C₆)alkyl)(SO₂—C₁–C₆)alkyl),—N((C₁–C₆)alkyl)(SO₂(C₃–C₆)cycloalkyl),—N((C₃–C₆)cycloalkyl)(SO₂—C₁–C₆)alkyl),—N((C₃–C₆)cycloalkyl)(SO₂(C₃–C₆)cycloalkyl), —O(C₁–C₆)alkyl,—O—SO₂(C₁–C₆)alkyl, —O—SO₂(C₃–C₆)cycloalkyl, —(CO)(C₁–C₆)alkyl,—(CO)CF₃, —(CO)(C₃–C₁₀)cycloalkyl, —(CO)(C₆–C₁₀)aryl,—(CO)(C₂–C₉)heterocyclyl, —(CO)(C₁–C₉)heteroaryl, —(CO)O(C₁–C₆)alkyl,—(CO)O(C₃–C₁₀)cycloalkyl, —(CO)O(C₆–C₁₀)aryl, —(CO)O(C₂–C₉)heterocyclyl,—(CO)O(C₁–C₉)heteroaryl, —(CO)(C₁–C₆)alkyl-O(C₁–C₆)alkyl,—SO₂(C₁–C₆)alkyl, —SO₂(C₃–C₆)cycloalkyl, SO₂CF₃, SO₂NH₂,SO₂NH(C₁–C₆)alkyl, —SO₂NH(C₃–C₆)cycloalkyl, —SO₂N((C₁–C₆)alkyl)₂,SO₂N((C₁–C₆)alkyl)((C₃–C₆)cycloalkyl), —SO₂N((C₃–C₆)cycloalkyl)₂ and—SO₂NR⁵R⁶, wherein said —(C₁–C₆)alkyl is optionally interrupted by oneto three elements selected from the group consisting of —(C═O), —SO₂,—S—, —O—, —N—, —NH— and —NR¹².

Moreover, the invention provides a compound of formula 1 wherein Ra isselected from the group consisting of hydrogen, halogen, hydroxy, —CF₃and —CN.

The invention also contemplates a compound of formula 1 wherein Rb isselected from the group consisting of hydrogen, —(C₁–C₆)alkyl,—(C₃–C₇)cycloalkyl and —(C₂–C₉)heterocyclyl.

The invention further provides a compound of formula 1 wherein each Rcindependently represents a substituent selected from the groupconsisting of hydrogen, hydroxy, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, and—(C₂–C₉)heterocyclyl, or two Rc substituents may be taken together withthe atom(s) to which they are attached to form a cyclic group,—(C₃–C₁₀)-cycloalkyl or —(C₂–C₉)-heterocyclyl.

The following is a non-limiting list of compounds according to thepresent invention:

-   N-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-methanesulfonamide;-   N-Methyl-N-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   Ethanesulfonic acid    methyl-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amide;-   N-(3-Methanesulfonylamino-5-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Ethyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-Methyl-N-(4-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-(5,6-Dimethyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-N-methyl-methanesulfonamide;-   Ethanesulfonic acid    methyl-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-amide;-   N-Ethyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   Ethanesulfonic acid    ethyl-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amide;-   4-{4-[2-(1-Methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Ethyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide;-   N-(2-{[2-(2-Oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   4-{4-[((R)-1-Methanesulfonyl-pyrrolidin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Methyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Methyl-N-(2-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Methyl-N-{3-[({methyl-[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-amino})-methyl]-phenyl}-methanesulfonamide;-   N-Methyl-N-(3-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Methyl-N-{4-methyl-3-[({methyl-[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-amino})-methyl]-phenyl}-methanesulfonamide;-   N-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-(5-Methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-(3-Fluoro-2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide;-   Ethanesulfonic acid    ethyl-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amide;-   4-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   4-{4-[2-((S)-1-Methanesulfonyl-pyrrolidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Ethyl-N-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   4-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   N-(2-Fluoro-6-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide;-   Ethanesulfonic acid    methyl-(3-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amide;-   N-(4-Fluoro-2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide;-   N-Cyclopropyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Methyl-N-(4-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-Methyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamide;-   N-{2,2-Dimethyl-3-[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-N-methyl-methanesulfonamide;-   N-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-4-yl)-methanesulfonamide;-   N-(2,4-Difluoro-6-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide;-   N-Cyclopropyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   3-{[2-(2-Oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-benzenesulfonamide;-   4-{4-[(1-Methanesulfonyl-piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-(3-{[2-(2-Oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Methyl-N-{2-[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-methanesulfonamide;    and-   N-Methyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide.

Also provided is a compound of formula I selected from the groupconsisting of:

-   N-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-methanesulfonamide;-   Ethanesulfonic acid    methyl-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amide;-   N-(3-Methanesulfonylamino-5-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Ethyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-(5,6-Dimethyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-N-methyl-methanesulfonamide;-   Ethanesulfonic acid    methyl-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-amide;-   N-Ethyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   Ethanesulfonic acid    ethyl-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amide;-   6-{4-[2-(1-Methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Ethyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide;-   N-(2-{[2-(2-Oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   6-{4-[((R)-1-Methanesulfonyl-pyrrolidin-2ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Methyl-N-{3-[({methyl-[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-amino})-methyl]-phenyl}-methanesulfonamide;-   N-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   Ethanesulfonic acid    ethyl-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amide;-   N-Ethyl-N-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-(2-Fluoro-6-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide;-   Ethanesulfonic acid    methyl-(3-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amide;-   N-Cyclopropyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Methyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamide;-   N-{2,2-Dimethyl-3-[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-N-methyl-methanesulfonamide;-   N-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-4-yl)-methanesulfonamide;-   N-(2,4-Difluoro-6-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide;-   N-Cyclopropyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   3-{[2-(2-Oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-benzenesulfonamide;-   6-{4-[(1-Methanesulfonyl-piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-(3-{[2-(2-Oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Methyl-N-{2-[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-methanesulfonamide;-   N-Methyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide;-   6-{4-[2-(1-Methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   6-{4-[(4-Methanesulfonyl-pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-(4-Methoxy-3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-{2,2-Dimethyl-3-[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide;-   N-(4-Methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   Ethanesulfonic acid    methyl-{3-[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-amide;-   N-(4-Fluoro-3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide;-   6-[4-(3-Methanesulfonylmethyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   Propane-1-sulfonic acid    methyl-{3-[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-amide;-   N-Methyl-N-(4-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   6-{4-[(6-Methanesulfonyl-pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   6-{4-[(5-Cyclopropyl-1H-pyrazol-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   6-{4-[(5-Methanesulfonyl-pyridin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-(3-Methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Methyl-N-(6-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-Isopropyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide;-   N-(4-Methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-(2-Methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   6-[4-(2-Methanesulfonylmethyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   N-Methyl-N-(3-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-Methyl-N-(5-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-Methyl-N-(4-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-Methyl-N-(2-methyl-5-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamide;-   N-Methyl-N-(5-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-Methyl-N-(6-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamide;-   N-Methyl-N-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamide;    and-   N-Methyl-N-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamide.

Further provided is a compound of formula I selected from the groupconsisting of:

-   N-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-methanesulfonamide;-   N-Methyl-N-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   Ethanesulfonic acid    methyl-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amide;-   N-(3-Methanesulfonylamino-5-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Ethyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-Methyl-N-(4-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-(5,6-Dimethyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-N-methyl-methanesulfonamide;-   Ethanesulfonic acid    methyl-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-amide;-   N-Ethyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   Ethanesulfonic acid    ethyl-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amide;-   7-{4-[2-(1-Methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Ethyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide;-   N-(2-{[2-(2-Oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   7-{4-[((R)-1-Methanesulfonyl-pyrrolidin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Methyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Methyl-N-(2-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Methyl-N-{3-[({methyl-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-amino})-methyl]-phenyl}-methanesulfonamide;-   N-Methyl-N-(3-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Methyl-N-{4-methyl-3-[({methyl-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-amino})-methyl]-phenyl}-methanesulfonamide;-   N-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-(5-Methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-(3-Fluoro-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide;-   Ethanesulfonic acid    ethyl-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amide;-   7-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   7-{4-[2-((S)-1-Methanesulfonyl-pyrrolidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Ethyl-N-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   7-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   N-(2-Fluoro-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide;-   Ethanesulfonic acid    methyl-(3-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amide;-   N-(4-Fluoro-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide;-   N-Cyclopropyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Methyl-N-(4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-Methyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamide;-   N-{2,2-Dimethyl-3-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-N-methyl-methanesulfonamide;-   N-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-4-yl)-methanesulfonamide;-   N-(2,4-Difluoro-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide;-   N-Cyclopropyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   3-{[2-(2-Oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-benzenesulfonamide;-   7-{4-[(1-Methanesulfonyl-piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-(3-{[2-(2-Oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Methyl-N-{2-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-methanesulfonamide;-   N-Methyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide;-   Methanesulfonic acid    3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl    ester;-   7-{4-[2-(1-Methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-(4-Fluoro-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   7-{4-[(4-Methanesulfonyl-pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-(4-Methoxy-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-{2,2-Dimethyl-3-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide;-   N-(4-Methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   Ethanesulfonic acid    methyl-{3-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-amide;-   N-(4-Fluoro-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide;-   7-[4-(3-Methanesulfonylmethyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   Propane-1-sulfonic acid    methyl-{3-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-amide;-   7-{4-[((S)-1-Methanesulfonyl-piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Methyl-N-(4-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   7-{4-[(6-Methanesulfonyl-pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   7-{4-[(5-Cyclopropyl-1H-pyrazol-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   7-{4-[(5-Methanesulfonyl-pyridin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-(3-Methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Methyl-N-(6-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-Isopropyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide;-   N-(4-Methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-(4,6-Dimethyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-N-methyl-methanesulfonamide;-   N-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-(2-Methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   7-[4-(2-Methanesulfonylmethyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   N-Methyl-N-(3-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-Methyl-N-(5-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-Methyl-N-(4-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-Methyl-N-(2-methyl-5-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamide;-   N-Methyl-N-(5-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-Methyl-N-(6-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamide;-   N-Methyl-N-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamide;-   N-Methyl-N-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamide;-   N-Methyl-N-(4-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamide;-   N-Methyl-N-(3-methyl-4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-Methyl-N-(5-methyl-4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-2-yl)-methanesulfonamide;-   N-Methyl-N-(6-methyl-5-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamide;-   N-Methyl-N-(6-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamide;-   N-Methyl-N-(5-methyl-4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-Methyl-N-(2-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-4-yl)-methanesulfonamide;-   N-Methyl-N-(6-methyl-4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-Methyl-N-(5-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-4-yl)-methanesulfonamide;-   N-Methyl-N-(5-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamide;-   N-Methyl-N-(5-methyl-4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamide;-   N-Methyl-N-(6-{([2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamide;-   N-Methyl-N-(6-methyl-4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-2-yl)-methanesulfonamide;-   N-Methyl-N-(2-methyl-4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamide;-   N-Methyl-N-(5-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamide;-   N-Methyl-N-(2-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamide;-   N-Methyl-N-(6-methyl-4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamide;-   N-Methyl-N-(4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-5-yl)-methanesulfonamide;-   N-Methyl-N-(2-methyl-5-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamide;-   N-Methyl-N-(4-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-5-yl)-methanesulfonamide;-   N-Methyl-N-(5-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-methanesulfonamide;-   N-Methyl-N-(5-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-methanesulfonamide;-   N-Methyl-N-(2-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-5-yl)-methanesulfonamide;-   N-Methyl-N-(3-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-methanesulfonamide;-   N-Methyl-N-(6-methyl-5-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamide;-   N-Methyl-N-(6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-Methyl-N-(4-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide;-   N-Methyl-N-(5-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamide;-   N-Methyl-N-(4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamide;-   N-Methyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamide;-   N-Methyl-N-(4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-2-yl)-methanesulfonamide;-   N-Methyl-N-(6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-methanesulfonamide;    and-   N-Methyl-N-(6-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-methanesulfonamide.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal, including a human, comprising administering tosaid mammal an amount of a compound of the formula 1, as defined above,or a pharmaceutically acceptable salt, solvate or prodrug thereof, thatis effective in treating abnormal cell growth. In one embodiment of thismethod, the abnormal cell growth is cancer, including, but not limitedto, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer ofthe head or neck, cutaneous or intraocular melanoma, uterine cancer,ovarian cancer, rectal cancer, cancer of the anal region, stomachcancer, colon cancer, breast cancer, uterine cancer, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease,cancer of the esophagus, cancer of the small intestine, cancer of theendocrine system, cancer of the thyroid gland, cancer of the parathyroidgland, cancer of the adrenal gland, sarcoma of soft tissue, cancer ofthe urethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers. In one embodimentthe method comprises comprising administering to a mammal an amount of acompound of formula 1 that is effective in treating said cancer solidtumor. In one preferred embodiment the solid tumor is breast, lung,colon, brain, prostate, stomach, pancreatic, ovarian, skin (melanoma),endocrine, uterine, testicular, and bladder cancer.

In another embodiment of said method, said abnormal cell growth is abenign proliferative disease, including, but not limited to, psoriasis,benign prostatic hypertrophy or restinosis.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal which comprises administering to said mammal anamount of a compound of formula 1, or a pharmaceutically acceptablesalt, solvate or prodrug thereof, that is effective in treating abnormalcell growth in combination with an anti-tumor agent selected from thegroup consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, antibodies, cytotoxics, anti-hormones, andanti-androgens.

This invention also relates to a pharmaceutical composition for thetreatment of abnormal cell growth in a mammal, including a human,comprising an amount of a compound of the formula 1, as defined above,or a pharmaceutically acceptable salt, solvate or prodrug thereof, thatis effective in treating abnormal cell growth, and a pharmaceuticallyacceptable carrier. In one embodiment of said composition, said abnormalcell growth is cancer, including, but not limited to, lung cancer, bonecancer, pancreatic cancer, skin cancer, cancer of the head or neck,cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,rectal cancer, cancer of the anal region, stomach cancer, colon cancer,breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers. In anotherembodiment of said pharmaceutical composition, said abnormal cell growthis a benign proliferative disease, including, but not limited to,psoriasis, benign prostatic hypertrophy or restinosis.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal which comprises administering to said mammal anamount of a compound of formula 1, or a pharmaceutically acceptablesalt, solvate or prodrug thereof, that is effective in treating abnormalcell growth in combination with another anti-tumor agent selected fromthe group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, antibodies, cytotoxics, anti-hormones, andanti-androgens. The invention also contemplates a pharmaceuticalcomposition for treating abnormal cell growth wherein the compositionincludes a compound of formula 1, as defined above, or apharmaceutically acceptable salt, solvate or prodrug thereof, that iseffective in treating abnormal cell growth, and another anti-tumor agentselected from the group consisting of mitotic inhibitors, alkylatingagents, anti-metabolites, intercalating antibiotics, growth factorinhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors,biological response modifiers, antibodies, cytotoxics; anti-hormones,and anti-androgens.

This invention also relates to a method for the treatment of a disorderassociated with angiogenesis in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the formula 1,as defined above, or a pharmaceutically acceptable salt, solvate orprodrug thereof, that is effective in treating said disorder incombination with one or more anti-tumor agents listed above. Suchdisorders include cancerous tumors such as melanoma; ocular disorderssuch as age-related macular degeneration, presumed ocular histoplasmosissyndrome, and retinal neovascularization from proliferative diabeticretinopathy; rheumatoid arthritis; bone loss disorders such asosteoporosis, Paget's disease, humoral hypercalcemia of malignancy,hypercalcemia from tumors metastatic to bone, and osteoporosis inducedby glucocorticoid treatment; coronary restenosis; and certain microbialinfections including those associated with microbial pathogens selectedfrom adenovirus, hantaviruses, Borrelia burgdorferi, Yersinia spp.,Bordetella pertussis, and group A Streptococcus.

This invention also relates to a method of (and to a pharmaceuticalcomposition for) treating abnormal cell growth in a mammal whichcomprise an amount of a compound of formula 1, or a pharmaceuticallyacceptable salt, solvate or prodrug thereof, in combination with anamount of one or more substances selected from anti-angiogenesis agents,signal transduction inhibitors, and antiproliferative agents, whichamounts are together effective in treating said abnormal cell growth.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II(cyclooxygenase II) inhibitors, can be used in conjunction with acompound of formula 1 in the methods and pharmaceutical compositionsdescribed herein. Examples of useful COX-II inhibitors include CELEBREX™(celecoxib), Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), andArcoxia (etoricoxib). Examples of useful matrix metalloproteinaseinhibitors are described in WO 96/33172 (published Oct. 24, 1996), WO96/27583 (published Mar. 7, 1996), European Patent Application No.97304971.1 (filed Jul. 8, 1997), European Patent Application No.99308617.2 (filed Oct. 29, 1999), WO 98/07697 (published Feb. 26, 1998),WO 98/03516 (published Jan. 29, 1998), WO 98/34918 (published Aug. 13,1998), WO 98/34915 (published Aug. 13, 1998), WO 98/33768 (publishedAug. 6, 1998), WO 98/30566 (published Jul. 16, 1998), European PatentPublication 606,046 (published Jul. 13, 1994), European PatentPublication 931,788 (published Jul. 28, 1999), WO 90/05719 (publishedMay 331, 1990), WO 99/52910 (published Oct. 21, 1999), WO 99/52889(published Oct. 21, 1999), WO 99/29667 (published Jun. 17, 1999), PCTInternational Application No. PCT/IB98/01113 (filed Jul. 21, 1998),European Patent Application No. 99302232.1 (filed Mar. 25, 1999), GreatBritain patent application number 9912961.1 (filed Jun. 3, 1999), U.S.Provisional Application No. 60/148,464 (filed Aug. 12, 1999), U.S. Pat.No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issuedJan. 19, 1999), and European Patent Publication 780,386 (published Jun.25, 1997), all of which are herein incorporated by reference in theirentirety. Preferred MMP-2 and MMP-9 inhibitors are those that havelittle or no activity inhibiting MMP-1. More preferred, are those thatselectively inhibit MMP-2 and/or MMP-9 relative to the othermatrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6,MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

Some specific examples of MMP inhibitors useful in combination with thecompounds of the present invention are AG-3340, RO 32-3555, RS 13-0830,and the compounds recited in the following list:

-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]-propionic    acid;-   3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic    acid hydroxyamide;-   (2R, 3R)    1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic    acid hydroxyamide;-   4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic    acid hydroxyamide;-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-amino]-propionic    acid;-   4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic    acid hydroxyamide;-   3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic    acid hydroxyamide;-   (2R, 3R)    1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic    acid hydroxyamide;-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)-amino]-propionic    acid;-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl)-amino]-propionic    acid;-   3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic    acid hydroxyamide;-   3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic    acid hydroxyamide; and-   3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic    acid hydroxyamide;

and pharmaceutically acceptable salts, solvates and prodrugs of saidcompounds.

VEGF inhibitors, for example, SU-11248, SU-5416 and SU-6668 (Sugen Inc.of South San Francisco, Calif., USA), can also be combined with acompound of formula 1. VEGF inhibitors are described in, for example inWO 99/24440 (published May 20, 1999), PCT International ApplicationPCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published Aug. 17,1995), WO 99/61422 (published Dec. 2, 1999), U.S. Pat. No. 5,834,504(issued Nov. 10, 1998), WO 98/50356 (published Nov. 12, 1998), U.S. Pat.No. 5,883,113 (issued Mar. 16, 1999), U.S. Pat. No. 5,886,020 (issuedMar. 23, 1999), U.S. Pat. No. 5,792,783 (issued Aug. 11, 1998), U.S.Pat. No. 6,653,308 (issued Nov. 25, 2003), WO 99/10349 (published Mar.4, 1999), WO 97/32856 (published Sep. 12, 1997), WO 97/22596 (publishedJun. 26, 1997), WO 98/54093 (published Dec. 3, 1998), WO 98/02438(published Jan. 22, 1998), WO 99/16755 (published Apr. 8, 1999), and WO98/02437 (published Jan. 22, 1998), all of which are herein incorporatedby reference in their entirety. Other examples of some specific VEGFinhibitors are IM862 (Cytran Inc. of Kirkland, Wash., USA); Avastin, ananti-VEGF monoclonal antibody of Genentech, Inc. of South San Francisco,Calif.; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder,Colo.) and Chiron (Emeryville, Calif.).

ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome plc), andthe monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of TheWoodlands, Tex., USA) and 2B-1 (Chiron), may be administered incombination with a compound of formula 1. Such erbB2 inhibitors includeHerceptin, 2C4, and pertuzumab. Such erbB2 inhibitors include thosedescribed in WO 98/02434 (published Jan. 22, 1998), WO 99/35146(published Jul. 15, 1999), WO 99/35132 (published Jul. 15, 1999), WO98/02437 (published Jan. 22, 1998), WO 97/13760 (published Apr. 17,1997), WO 95/19970 (published Jul. 27, 1995), U.S. Pat. No. 5,587,458(issued Dec. 24, 1996), and U.S. Pat. No. 5,877,305 (issued Mar. 2,1999), each of which is herein incorporated by reference in itsentirety. ErbB2 receptor inhibitors useful in the present invention arealso described in U.S. Provisional Application No. 60/117,341, filedJan. 27, 1999, and in U.S. Provisional Application No. 60/117,346, filedJan. 27, 1999, both of which are herein incorporated by reference intheir entirety. Other erbb2 receptor inhibitors include TAK-165 (Takeda)and GW-572016 (Glaxo-Wellcome).

Various other compounds, such as styrene derivatives, have also beenshown to possess tyrosine kinase inhibitory properties, and some oftyrosine kinase inhibitors have been identified as erbB2 receptorinhibitors. More recently, five European patent publications, namely EP0 566 226 A1 (published Oct. 20, 1993), EP 0 602 851 A1 (published Jun.22, 1994), EP 0 635 507 A1 (published Jan. 25, 1995), EP 0 635 498 A1(published Jan. 25, 1995), and EP 0 520 722 A1 (published Dec. 30,1992), refer to certain bicyclic derivatives, in particular quinazolinederivatives, as possessing anti-cancer properties that result from theirtyrosine kinase inhibitory properties. Also, World Patent Application WO92/20642 (published Nov. 26, 1992), refers to certain bis-mono andbicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitorsthat are useful in inhibiting abnormal cell proliferation. World PatentApplications WO96/16960 (published Jun. 6, 1996), WO 96/09294 (publishedMar. 6, 1996), WO 97/30034 (published Aug. 21, 1997), WO 98/02434(published Jan. 22, 1998), WO 98/02437 (published Jan. 22, 1998), and WO98/02438 (published Jan. 22, 1998), also refer to substituted bicyclicheteroaromatic derivatives as tyrosine kinase inhibitors that are usefulfor the same purpose. Other patent applications that refer toanti-cancer compounds are World Patent Application WO00/44728 (publishedAug. 3, 2000), EP 1029853A1 (published Aug. 23, 2000), and WO01/98277(published Dec. 12, 2001) all of which are incorporated herein byreference in their entirety.

Other antiproliferative agents that may be used with the compounds ofthe present invention include inhibitors of the enzyme farnesyl proteintransferase and inhibitors of the receptor tyrosine kinase PDGFr,including the compounds disclosed and claimed in the following U.S.patent applications: U.S. Ser. No. 09/221,946 (filed Dec. 28, 1998);U.S. Ser. No. 09/454,058 (filed Dec. 2, 1999); U.S. Ser. No. 09/501,163(filed Feb. 9, 2000); U.S. Ser. No. 09/539,930 (filed Mar. 31, 2000);U.S. Ser. No. 09/202,796 (filed May 22, 1997); U.S. Ser. No. 09/384,339(filed Aug. 26, 1999); and U.S. Ser. No. 09/383,755 (filed Aug. 26,1999); and the compounds disclosed and claimed in the following U.S.provisional patent applications: 60/168,207 (filed Nov. 30, 1999);60/170,119 (filed Dec. 10, 1999); 60/177,718 (filed Jan. 21, 2000);60/168,217 (filed Nov. 30, 1999), and 60/200,834 (filed May 1, 2000).Each of the foregoing patent applications and provisional patentapplications is herein incorporated by reference in their entirety.

A compound of formula 1 may also be used with other agents useful intreating abnormal cell growth or cancer, including, but not limited to,agents capable of enhancing antitumor immune responses, such as CTLA4(cytotoxic lymphocyte antigen 4) antibodies, and other agents capable ofblocking CTLA4; and anti-proliferative agents such as other farnesylprotein transferase inhibitors, for example the farnesyl proteintransferase inhibitors described in the references cited in the“Background” section, supra. Specific CTLA4 antibodies that can be usedin the present invention include those described in U.S. ProvisionalApplication 60/113,647 (filed Dec. 23, 1998) which is hereinincorporated by reference in its entirety.

A compound of formula I may be applied as a sole therapy or may involveone or more other anti-tumor substances, for example those selectedfrom, for example, mitotic inhibitors, for example vinblastine;alkylating agents, for example cis-platin, oxaliplatin, carboplatin andcyclophosphamide; anti-metabolites, for example 5-fluorouracil,capecitabine, cytosine arabinoside and hydroxyurea, or, for example, oneof the preferred anti-metabolites disclosed in European PatentApplication No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; growth factor inhibitors; cell cycle inhibitors; intercalatingantibiotics, for example adriamycin and bleomycin; enzymes, for exampleinterferon; and anti-hormones, for example anti-estrogens such asNolvadex (tamoxifen) or, for example anti-androgens such as Casodex(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).

The compounds of the present invention may be used alone or incombination with one or more of a variety of anti-cancer agents orsupportive care agents. For example, the compounds of the presentinvention may be used with cytotoxic agents, e.g., one or more selectedfrom the group consisting of a camptothecin, irinotecan HCl (Camptosar),edotecarin, SU-11248, epirubicin (Ellence), docetaxel (Taxotere),paclitaxel, rituximab (Rituxan) bevacizumab (Avastin), imatinib mesylate(Gleevac), Erbitux, gefitinib (Iressa), and combinations thereof. Theinvention also contemplates the use of the compounds of the presentinvention together with hormonal therapy, e.g., exemestane (Aromasin),Lupron, anastrozole (Arimidex), tamoxifen citrate (Nolvadex), Trelstar,and combinations thereof. Further, the invention provides a compound ofthe present invention alone or in combination with one or moresupportive care products, e.g., a product selected from the groupconsisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin,Procrit, Aloxi, Emend, or combinations thereof. Such conjoint treatmentmay be achieved by way of the simultaneous, sequential or separatedosing of the individual components of the treatment.

The compounds of the invention may be used with antitumor agents,alkylating agents, antimetabolites, antibiotics, plant-derived antitumoragents, camptothecin derivatives, tyrosine kinase inhibitors,antibodies, interferons, and/or biological response modifiers. In thisregard, the following is a non-limiting list of examples of secondaryagents that may be used with the compounds of the invention.

-   -   Alkylating agents include, but are not limited to, nitrogen        mustard N-oxide, cyclophosphamide, ifosfamide, melphalan,        busulfan, mitobronitol, carboquone, thiotepa, ranimustine,        nimustine, temozolomide, AMD-473, altretamine, AP-5280,        apaziquone, brostallicin, bendamustine, carmustine,        estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170,        mafosfamide, and mitolactol; platinum-coordinated alkylating        compounds include but are not limited to, cisplatin,        carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin or        satrplatin;    -   Antimetabolites include but are not limited to, methotrexate,        6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU)        alone or in combination with leucovorin, tegafur, UFT,        doxifluridine, carmofur, cytarabine, cytarabine ocfosfate,        enocitabine, S-1, gemcitabine, fludarabin, 5-azacitidine,        capecitabine, cladribine, clofarabine, decitabine, eflornithine,        ethynylcytidine, cytosine arabinoside, hydroxyurea, TS-1,        melphalan, nelarabine, nolatrexed, ocfosfate, disodium        premetrexed, pentostatin, pelitrexol, raltitrexed, triapine,        trimetrexate, vidarabine, vincristine, vinorelbine; or for        example, one of the preferred anti-metabolites disclosed in        European Patent Application No. 239362 such as        N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic        acid;    -   Antibiotics include but are not limited to: aclarubicin,        actinomycin D, amrubicin, annamycin, bleomycin, daunorubicin,        doxorubicin, elsamitrucin, epirubicin, galarubicin, idarubicin,        mitomycin C, nemorubicin, neocarzinostatin, peplomycin,        pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin        or zinostatin;    -   Hormonal therapy agents, e.g., exemestane (Aromasin), Lupron,        anastrozole (Arimidex), doxercalciferol, fadrozole, formestane,        anti-estrogens such as tamoxifen citrate (Nolvadex) and        fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene,        letrozole (Femara), or anti-androgens such as bicalutamide,        flutamide, mifepristone, nilutamide, Casodex®        (4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide)        and combinations thereof;    -   Plant derived anti-tumor substances include for example those        selected from mitotic inhibitors, for example vinblastine,        docetaxel (Taxotere) and paclitaxel;    -   Cytotoxic topoisomerase inhibiting agents include one or more        agents selected from the group consisting of aclarubicn,        amonafide, belotecan, camptothecin, 10-hydroxycamptothecin,        9-aminocamptothecin, diflomotecan, irinotecan HCl (Camptosar),        edotecarin, epirubicin (Ellence), etoposide, exatecan,        gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone,        rubitecan, sobuzoxane, SN-38, tafluposide, and topotecan, and        combinations thereof;    -   Immunologicals include interferons and numerous other immune        enhancing agents. Interferons include interferon alpha,        interferon alpha-2a, interferon, alpha-2b, interferon beta,        interferon gamma-1a or interferon gamma-n1. Other agents include        filgrastim, lentinan, sizofilan, TheraCys, ubenimex, WF-10,        aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab,        denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod,        lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim,        OncoVAX-CL, sargramostim, tasonermin, tecleukin, thymalasin,        tositumomab, Virulizin, Z-100, epratuzumab, mitumomab,        oregovomab, pemtumomab, Provenge;    -   Biological response modifiers are agents that modify defense        mechanisms of living organisms or biological responses, such as        survival, growth, or differentiation of tissue cells to direct        them to have anti-tumor activity. Such agents include krestin,        lentinan, sizofiran, picibanil, or ubenimex;    -   Other anticancer agents include alitretinoin, ampligen,        atrasentan bexarotene, bortezomib. Bosentan, calcitriol,        exisulind, finasteride, fotemustine, ibandronic acid,        miltefosine, mitoxantrone, l-asparaginase, procarbazine,        dacarbazine, hydroxycarbamide, pegaspargase, pentostatin,        tazarotne, TLK-286, Velcade, Tarceva, or tretinoin;    -   Other anti-angiogenic compounds include acitretin, fenretinide,        thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide,        combretastatin A-4, endostatin, halofuginone, rebimastat,        removab, Revlimid, squalamine, ukrain and Vitaxin;    -   Platinum-coordinated compounds include but are not limited to,        cisplatin, carboplatin, nedaplatin, or oxaliplatin;    -   Camptothecin derivatives include but are not limited to        camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin,        irinotecan, SN-38, edotecarin, and potecan;    -   Tyrosine kinase inhibitors are Iressa or SU5416;    -   Antibodies include Herceptin, Erbitux, Avastin, or Rituximab;    -   Interferons include interferon alpha, interferon alpha-2a,        interferon, alpha-2b, interferon beta, interferon gamma-1a or        interferon gamma-n1;    -   Biological response modifiers are agents that modify defense        mechanisms of living organisms or biological responses, such as        survival, growth, or differentiation of tissue cells to direct        them to have anti-tumor activity. Such agents include krestin,        lentinan, sizofiran, picibanil, or ubenimex; and    -   Other antitumor agents include mitoxantrone, I-asparaginase,        procarbazine, dacarbazine, hydroxycarbamide, pentostatin, or        tretinoin.

“Abnormal cell growth”, as used herein, unless otherwise indicated,refers to cell growth that is independent of normal regulatorymechanisms (e.g., loss of contact inhibition). This includes theabnormal growth of: (1) tumor cells (tumors) that proliferate byexpressing a mutated tyrosine kinase or overexpression of a receptortyrosine kinase; (2) benign and malignant cells of other proliferativediseases in which aberrant tyrosine kinase activation occurs; (4) anytumors that proliferate by receptor tyrosine kinases; (5) any tumorsthat proliferate by aberrant serine/threonine kinase activation; and (6)benign and malignant cells of other proliferative diseases in whichaberrant serine/threonine kinase activation occurs.

The compounds of the present invention are potent inhibitors of the FAKprotein tyrosine kinases, and thus are all adapted to therapeutic use asantiproliferative agents (e.g., anticancer), antitumor (e.g., effectiveagainst solid tumors), antiangiogenesis (e.g., stop or preventproliferationation of blood vessels) in mammals, particularly in humans.In particular, the compounds of the present invention are useful in theprevention and treatment of a variety of human hyperproliferativedisorders such as malignant and benign tumors of the liver, kidney,bladder, breast, gastric, ovarian, colorectal, prostate, pancreatic,lung, vulval, thyroid, hepatic carcinomas, sarcomas, glioblastomas, headand neck, and other hyperplastic conditions such as benign hyperplasiaof the skin (e.g., psoriasis) and benign hyperplasia of the prostate(eq., BPH). It is, in addition, expected that a compound of the presentinvention may possess activity against a range of leukemias and lymphoidmalignancies.

In one preferred embodiment of the present invention cancer is selectedfrom lung cancer, bone cancer, pancreatic cancer, gastric, skin cancer,cancer of the head or neck, cutaneous or intraocular melanoma, uterinecancer, ovarian cancer, gynecological, rectal cancer, cancer of the analregion, stomach cancer, colon cancer, breast cancer, uterine cancer,carcinoma of the fallopian tubes, carcinoma of the endometrium,carcinoma of the cervix, carcinoma of the vagina, carcinoma of thevulva, Hodgkin's Disease, cancer of the esophagus, cancer of the smallintestine, cancer of the endocrine system, cancer of the thyroid gland,cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma ofsoft tissue, cancer of the urethra, cancer of the penis, squamous cell,prostate cancer, chronic or acute leukemia, lymphocytic lymphomas,cancer of the bladder, cancer of the kidney or ureter, renal cellcarcinoma, carcinoma of the renal pelvis, neoplasms of the centralnervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain,pituitary adenoma, or a combination of one or more of the foregoingcancers.

In a more preferred embodiment cancer is selected a solid tumor, suchas, but not limited to, breast, lung, colon, brain, prostate, stomach,pancreatic, ovarian, skin (melanoma), endocrine, uterine, testicular,and bladder.

The compounds of the present invention may also be useful in thetreatment of additional disorders in which aberrant expressionligand/receptor interactions or activation or signalling events relatedto various protein tyrosine kinases, are involved. Such disorders mayinclude those of neuronal, glial, astrocytal, hypothalamic, and otherglandular, macrophagal, epithelial, stromal, and blastocoelic nature inwhich aberrant function, expression, activation or signalling of theerbB tyrosine kinases are involved. In addition, the compounds of thepresent invention may have therapeutic utility in inflammatory,angiogenic and immunologic disorders involving both identified and asyet unidentified tyrosine kinases that are inhibited by the compounds ofthe present invention.

A particular aspect of this invention is directed to methods fortreating or preventing a condition that presents with low bone mass in amammal (including a human being) which comprise administering to amammal in need of such treatment a condition that presents with low bonemass treating amount of a Formula I compound or a pharmaceuticallyacceptable salt of said compound.

This invention is particularly directed to such methods wherein thecondition that presents with low bone mass is osteoporosis, frailty, anosteoporotic fracture, a bone defect, childhood idiopathic bone loss,alveolar bone loss, mandibular bone loss, bone fracture, osteotomy,periodontitis or prosthetic ingrowth.

A particular aspect of this invention is directed to methods fortreating osteoporosis in a mammal (including a human being) whichcomprise administering to a mammal in need of such treatment anosteoporosis treating amount of a Formula I compound or apharmaceutically acceptable salt of said compound.

Another aspect of this invention is directed to methods for treating abone fracture or an osteoporotic fracture in a mammal which compriseadministering to a mammal in need of such treatment a bone fracturetreating or an osteoporotic fracture treating amount of a Formula Icompound or a pharmaceutically acceptable salt of said compound.

The term “osteoporosis” includes primary osteoporosis, such as senile,postmenopausal and juvenile osteoporosis, as well as secondaryosteoporosis, such as osteoporosis due to hyperthyroidism or Cushingsyndrome (due to corticosteroid use), acromegaly, hypogonadism,dysosteogenesis and hypophospatasemia.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as hereinbefore defined in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined with a pharmaceuticallyacceptable adjuvant, diluent or carrier.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated. The daily dosage ofthe compound of formula (I)/salt/solvate (active ingredient) may be inthe range from 1 mg to 1 gram, preferably 1 mg to 250 mg, morepreferably 10 mg to 100 mg.

The present invention also encompasses sustained release compositions.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula 1 can be prepared using the synthetic routeoutlined in Scheme 1. The substituents in Scheme 1 have the same meaningas the substituents defined for formula 1.

Compounds of formula 1 can be prepared starting from the amine (2) andpyrimidine (3). Combining 3 with a Lewis Acid at temperatures rangingfrom −15 to 45° C. for a time period of 10–60 minutes in an inertsolvent (or solvent mixture) followed by addition of 2 and a suitablebase provides after the period of 1–24 h the intermediate4-chloropyrimidine (4) in high yields. Examples of inert solventsinclude but are not limited to THF, 1,4-dioxane, n-BuOH, i-PrOH,dichloromethane and 1,2-dichloroethane. Examples of suitable basesemployed may include but are not limited to (i) non-nucleophilic organicbases for example triethylamine or diisopropylethylamine (ii) inorganicbases such as potassium carbonate or cesium carbonate or (iii) resinbound bases such as MP-carbonate.

Examples of Lewis Acids include but are not limited to halide salts ofmagnesium, copper, zinc, tin or titanium. In the next reaction,intermediate 4 is reacted with an amine of the formula 5 either neat orin the presence of an inert solvent (or solvent mixture) at temperaturesranging from 0 to 150° C. to provide the compounds of formula 1.Optionally this reaction can be run in the presence of a suitable base.Examples of suitable solvents for this reaction include but are notlimited to THF, 1,4-dioxane, DMF, N-methyl-pyrrolidinone, EtOH, n-BuOH,i-PrOH, dichloromethane, 1,2-dichloroethane, DMSO or acetonitrile.Suitable bases are as outlined above.

Compounds of the present invention may be synthetically transformed intoother compounds of the invention by techniques known to those skilled inthe art. Simply for illustrative purposes and without limitation, suchmethods include:

a) removal of a protecting group by methods outlined in T. W. Greene andP. G. M. Wuts, “Protective Groups in Organic Synthesis”, Second Edition,John Wiley and Sons, New York, 1991; e.g., emoval of a BOC protectinggroup with an acid source such as HCl or trifluoroacetic acid.

b) displacement of a leaving group (halide, mesylate, tosylate, etc)with functional groups such as but not limited to a primary or secondaryamine, thiol or alcohol to form a secondary or tertiary amine, thioetheror ether, respectively.

c) treatment of phenyl (or substituted phenyl) carbamates with primaryof secondary amines to form the corresponding ureas as in Thavonekham, Bet. al. Synthesis (1997), 10, p 1189;

d) reduction of propargyl or homopropargyl alcohols or N-BOC protectedprimary amines to the corresponding E-allylic or E-homoallylicderivatives by treatment with sodium bis(2-methoxyethoxy)aluminumhydride (Red-AI) as in Denmark, S. E.; Jones, T. K. J. Org. Chem. (1982)47, 4595–4597 or van Benthem, R. A. T. M.; Michels, J. J.; Speckamp, W.N. Synlett (1994), 368–370;

e) reduction of alkynes to the corresponding Z-alkene derivatives bytreatment hydrogen gas and a Pd catalyst as in Tomassy, B. et. al.Synth. Commun. (1998), 28, p 1201

f) treatment of primary and secondary amines with an isocyanate, acidchloride (or other activated carboxylic acid derivative), alkyl/arylchloroformate or sulfonyl chloride to provide the corresponding urea,amide, carbamate or sulfonamide;

g) reductive amination of a primary or secondary amine using an aldehydeor ketone and an appropriate reducing reagent.

h) treatment of alcohols with an isocyanate, acid chloride (or otheractivated carboxylic acid derivative), alkyl/aryl chloroformate orsulfonyl chloride to provide the corresponding carbamate, ester,carbonate or sulfonic acid ester.

Amines of the formula 5 may be purchased and used directly oralternatively be prepared by one skilled in the art using ordinarychemical transformations. For example; arylalkylamines orheteroarylalkylamines may be prepared from the corresponding nitrile bycatalytic hydrogenation using catalysts such as Pd/C or Raney Nickel orby lithium aluminum hydride reduction, (see Rylander, CatalyticHydrogenation in Organic Synthesis, Academic Press, 1979).

The nitrile starting materials can be either purchased or prepared fromthe corresponding aryl/heteroaryl bromide, iodide or triflate andZN(CN)2 using Pd coupling conditions found in Tschaen, D. M., et. alSynthetic Communications (1994), 24, 6, pp 887–890.

Heteroaryl nitriles can be prepared by nucleophilic addition of analkali metal cyanide an alkylsulfonylated heteroaromatic system in aninert solvent at temperatures ranging from 22–100° C.

Alternatively, nitriles can be prepared by dehydration of thecorresponding primary amide derivative using trifluoroacetic anhydrideand pyridine in an inert solvent.

Benzyl or heteroarylmethylamines can be prepared by reacting theappropriate arylalkyl or heteroarylalkyl halide and the potassium saltof (BOC)₂NH and subsequent removal of the BOC groups with acid.

Amines, protected forms of amines, precursors to amines and precursorsto the protected forms of amines of formula 5 can be prepared bycombining the appropriate alkyne, or alkenyl stannane, alkenyl borane,alkenyl boronic acid, boronic ester with the appropriate aryl orheteroaryl bromide, iodide or triflate using Pd coupling conditions asfound in Tsuji, J.; Palladium Reagents and Catalysis, John Wiley andSons 1999 and references cited therein.

Appropriately protected amines of formula 5 may be converted todifferent amines of formula 5 according to methods familiar to thoseskilled in the art for example as but limited to:

(a) oxidation of a thioether to a sulfoxide or sulfone.

(b) N-alkylation of a sulfanilide can be achieved under phase transferusing conditions described by Brehme, R. “Synthesis”, (1976), pp113–114.

N-aryl sulfonamides may be prepared by the reaction of an appropriatelysubstituted 2-fluorobenzylnitrile with a sulfonamide using cesiumcarbonate or potassium carbonate in an inert solvent at a temperature of22–100° C.

N-heteroaryl sulfonamides may be prepared by the reaction of theappropriately substituted halogenated pyridine, pyrimidine or pyrazinewith a sulfonamide using cesium carbonate in an inert solvent at atemperature of 22–100° C.

Alternatively, N-heteroaryl sulfonamides may be prepared fromheteroaromaic N-oxides by displacement of a halogen with a sulfonamideanion using cesium carbonate in an inert solvent in a sealed tube at atemperature of 70° C.

As understood by those skilled in the art, the chemical transformationto convert an aryl halide or triflate or heteroaryl halide or triflateto an aromatic or heteroaromatic amine may be carried out usingconditions currently outlined in the literature, see Hartwig, J. F.:“Angew. Chem. Int. Ed.” (1998), 37, pp. 2046–2067, Wolfe, J. P.; Wagaw,S.; Marcoux, J. F.; Buchwald, S. L.; “Acc. Chem. Res.”, (1998), 31, pp805–818, Wolfe, J. P.; Buchwald, S. L.; “J. Org. Chem.”, (2000), 65, pp1144–1157, Muci, A. R.; Buchwald, S. L.; “Topics in Current Chemistry”(2002), pp 131–209 and references cited therein. Further, as understoodby those skilled in the art, these same aryl or heteroaryl aminatiionchemical transformations may alternatively be carried out on nitrile (orprimary amide) precursors which provide amines of the formula 5 afternitrile (or amide) reduction. Protected amines of formula 5 may befurther converted to different amines of formula 5 according to methodsfamiliar to those skilled in the art.

The in vitro activity of the compounds of formula 1 may be determined bythe following procedure. More particularly, the following assay providesa method to determine whether compounds of the formula 1 inhibit thetyrosine kinase activity of the catalytic construct FAK(410-689). Theassay is an ELISA-based format, measuring the inhibition of poly-glu-tyrphosphorylation by FAK(410-689).

The assay protocol has three parts:

-   -   I. Purification and cleavage of His-FAK(410-689)    -   II. FAK410-689 (a.k.a. FAKcd) Activation    -   III. FAKcd Kinase ELISA        Materials:    -   Ni-NTA agarose (Qiagen)    -   XK-16 column (Amersham-Pharmacia)    -   300 mM Imidizole    -   Superdex 200 HiLoad 16/60 prep grade column (Amersham Biotech.)    -   Antibody: Anti-Phosphotyrosine HRP-Conjugated Py20 (Transduction        labs)    -   FAKcd: Purified and activated in house    -   TMB Microwell Peroxidase Substrate (Oncogene Research Products        #CL07)    -   BSA: Sigma #A3294    -   Tween-20: Sigma #P1379    -   DMSO: Sigma #D-5879    -   D-PBS: Gibco #14190-037.        Reagents for Purification:    -   Buffer A: 50 mM HEPES pH 7.0    -   500 mM NaCl    -   0.1 mM TCEP    -   Complete™ protease inhibitor cocktail tablets (Roche)    -   Buffer B: 25 mM HEPES pH 7.0    -   400 mM NaCl    -   0.1 mM TCEP    -   Buffer C: 10 mM HEPES pH 7.5    -   200 mM Ammonium Sulfate    -   0.1 mM TCEP        Reagents for Activation    -   FAK(410-689): 3 tubes of frozen aliquots at 150 ul/tube for a        total of 450 ul at 1.48 mg/ml (660 ug)    -   His-Src(249-524): ˜0.74 mg/ml stock in 10 mM HEPES, 200 mM        (NH4)2SO4    -   Src reaction buffer (Upstate Biotech):        -   100 mM Tris-HCl pH7.2,        -   125 mM MgCl2,        -   25 mM MnCl2,        -   2 mM EDTA,        -   250 uM Na3VO4,        -   2 mM DTT.    -   Mn2+/ATP cocktail (Upstate Biotech)        -   75 mM MnCl2,        -   500 uM ATP,        -   20 mM MOPS pH 7.2,        -   1 mM Na3VO4,        -   25 mM □-glycerol phosphate,        -   5 mM EGTA,        -   1 mM DTT.    -   ATP: 150 mM stock    -   MgCl₂: 1 M Stock    -   DTT: 1M stock        Reagents for FAKcd Kinase ELISA    -   Phosphorylation Buffer:        -   50 mM HEPES, pH 7.5,        -   125 mM NaCl,        -   48 mM MgCl2.    -   Wash Buffer: TBS+0.1% Tween-20.    -   Blocking Buffer:        -   Tris Buffer Saline,        -   3% BSA,        -   0.05% Tween-20, filtered.    -   Plate Coating Buffer:        -   50 mg/ml Poly-Glu-Tyr (Sigma #P0275) in Phosphate buffer            Saline (DPBS).    -   ATP: 0.1M ATP in H2O or HEPES, pH7.        -   Note: ATP Assay Buffer:        -   Make up as 75 uM ATP in PBS, so that 80 ul in        -   120 ul reaction volume=50 uM final ATP concentration.            I. Purification of His-FAKcd(410-689)

1. Resuspend 130 g baculovirus cell paste containing the over expressedHis-FAKcd410-689 recombinant protein in 3 volumes (400 ml) of Buffer A.

2. Lyse cells with one pass on a microfluidizer.

3. Remove cell debris by centrifugation at 4OC for 35 minutes at 14,000rpm in a Sorval SLA-1500 rotor.

4. Transfer the supernatant to a clean tube and add 6.0 ml of Ni-NTAagarose (Qiagen).

5. Incubate the suspension with gentle rocking at 4OC for 1 hour.

6. Centrifuge suspension at 700×g in a swinging bucket rotor.

7. Discard the supernatant and resuspend the agarose beads in 20.0 ml ofBuffer A.

8. Transfer the beads to an XK-16 column (Amersham-Pharmacia) connecteda FPLC™.

9. Wash the agarose-beads with 5 column volumes of Buffer A and eluteoff the column with a step gradient of Buffer A containing 300 mMImidizole.

10. Perform a buffer exchange of the eluted fractions into Buffer B.

11. Following buffer exchange, pool the fractions and add thrombin at a1:300 (w/w) ratio and incubated overnight at 13° C. to remove theN-terminal His-tag (His-FAK410-698→FAK410-689 (a.k.a. FAKcd)).

12. Add the reaction mixture back onto the Ni-NTA column equilibratedwith Buffer A and collect the flow-through.

13. Concentrate the flow-through down to 1.7 ml and load directly onto aSuperdex 200 HiLoad 16/60 prep grade column equilibrated with Buffer C.The desired protein elutes between 85–95 ml.

14. Aliquot the FAKcd protein and store frozen at −80° C.

II. FAK Activation

1. To 450 ul of FAK(410-689) at 1.48 mg/ml (660 ug) add the following:

-   -   30 ul of 0.037 mg/ml (1 uM) His-Src(249-524)    -   30 ul of 7.5 mM ATP    -   12 ul of 20 mM MgCl2    -   10 ul Mn2+/ATP cocktail (UpState Biotech.)    -   4 ul of 6.7 mM DTT    -   60 ul Src Reaction Buffer (UpState Biotech.)

2. Incubate Reaction for at least 3 hours at room temperature

At time t₀, almost all of the FAK(410-689) is singly phosphorylated. Thesecond phosphorylation is slow. At t₁₂₀ (t=120 minutes), add 10 ul of150 mM ATP.

T₀=(Start) 90% singly phosphorylated FAK(410-689) (1 PO4)

T₄₃=(43 min) 65% singly phosphorylated (1 PO4), 35% doublyphosphorylated (2 PO4)

T₉₀=(90 min) 45% 1 PO4, 55% 2 PO4

T₁₅₀=15% 1 PO4, 85% 2 PO4

T₂₁₀=<10% 1 PO4, >90% 2 PO4 desalted sample

3. Add 180 ul aliquots of the desalted material to NiNTA spin column andincubate on spin column.

4. Spin at 10 k rpm (microfuge), for 5 min to isolate and collect flowthrough (Activated FAK(410-689)) and remove His-Src (captured oncolumn).

III. FAKcd Kinase ELISA

1. Coat 96-well Nunc MaxiSorp plates with poly-glu-tyr (pGT) at 10ug/well: Prepare 10 ug/ml of pGT in PBS and aliquot 100 ul/well.Incubate the plates at 37° C. overnight, aspirate the supernatant, washthe plates 3 times with Wash Buffer, and flick to dry before storing at4° C.

2. Prepare compound stock solutions of 2.5 mM in 100% DMSO. The stocksare subsequently diluted to 60× of the final concentration in 100% DMSO,and diluted 1:5 in Kinase Phosphorylation Buffer.

3. Prepare a 75 uM working ATP solution in Kinase phosphorylationbuffer. Add 80 ul to each well for a final ATP concentration of 50 uM.

4. Transfer 10 ul of the diluted compounds (0.5 log serial dilutions) toeach well of the pGT assay plate, running each compound in triplicateson the same plate.

5. Dilute on ice, FAKcd protein to 1:1000 in Kinase PhosphorylationBuffer. Dispense 30 ul per well.

6. Note: Linearity and the appropriate dilution must be pre-determinedfor each batch of protein. The enzyme concentration selected should besuch that quantitation of the assay signal will be approximately 0.8–1.0at OD450, and in the linear range of the reaction rate.

7. Prepare both a No ATP control (noise) and a No Compound Control(Signal).

8. (Noise) One blank row of wells receives 10 ul of 1:5 dilutedcompounds in DMSO, 80 ul of Phosphorylation buffer (minus ATP), and 30ul FAKcd solution.

9. (Siganl) Control wells receive 10 ul of 1:5 diluted DMSO (minusCompound) in Kinase phosphorylation buffer, 80 ul of 75 uM ATP, and 30ul of 1:1000 FAKcd enzyme.

10. Incubate reaction at room temperature for 15 minutes with gentleshaking on a plate shaker.

11. Terminate the reaction by aspirating off the reaction mixture andwashing 3 times with wash buffer.

12. Dilute phospho-tyrosine HRP-conjugated (pY20HRP) antibody to 0.250ug/ml (1:1000 of Stock) in blocking buffer. Dispense 100 ul per well,and incubate with shaking for 30 min. at R.T.

13. Aspirate the supernatant and wash the plate 3 times with washbuffer.

14. Add 100 ul per well of room temperature TMB solution to initiatecolor development. Color development is terminated after approximately15–30 sec. by the addition of 100 ul of 0.09M H2SO4 per well.

15. The signal is quantitated by measurement of absorbance at 450 nm onthe BioRad microplate reader or a microplate reader capable of readingat OD450.

16. Inhibition of tyrosine kinase activity would result in a reducedabsorbance signal. The signal is typically 0.8–1.0 OD units. The valuesare reported as IC_(50s), uM concentration.

FAK Inducible Cell-based ELISA

Materials:

Reacti-Bind Goat Anti-Rabbit Plates 96-well (Pierce Product#15135ZZ@115.00 USD)

FAKpY397 rabbit polyclonal antibody (Biosource #44624 @315.00 USD)

ChromePure Rabbit IgG, whole molecule (Jackson Laboratories #001-000-003@60/25 mg USD)

UBI αFAK clone 2A7 mouse monoclonal antibody (Upstate#05-182 @289.00USD)

Peroxidase-conjugated AffiniPure Goat Anti-Mouse IgG (Jackson Labs#115-035-146 @95/1.5 ml USD)

SuperBlock TBS (Pierce Product#37535ZZ @99 USD)

Bovine Serum Albumin (Sigma #A-9647 @117.95/100 g USD)

TMB Peroxidase substrate (Oncogene Research Products #CL07–100 ml @40.00USD)

Na3VO4 Sodium Orthovanadate (Sigma #S6508 @43.95/50 g USD)

MTT substrate (Sigma # M-2128 @25.95/500 mg USD)

Growth Media: DMEM+10% FBS, P/S, Glu, 750 ug/ml Zeocin and 50 ug/mlHygromycin (Zeocin InVitrogen #R250-05 @725 USD and HygromyconInVitrogen #R220-05 @150 USD)

Mifepristone InVitrogen # H110-01 @125 USD

Complete™ EDTA-free Protease Inhibitor pellet Boehringer Mannheim#1873580

FAK cell-based Protocol for selectivity of kinase-dependentphosphoFAKY397

Procedure:

An inducible FAK cell-based assay in ELISA format for the screening ofchemical matter to identify tyrosine kinase specific inhibitors wasdeveloped. The cell-based assay exploits the mechanism of theGeneSwitch™ system (InVitrogen) to exogenously control the expressionand phosphorylation of FAK and the kinase-dependent autophosphorylationsite at residue Y397.

Inhibition of the kinase-dependent autophosphorylation at Y397 resultsin a reduced absorbance signal at OD450. The signal is typically 0.9 to1.5 OD450 units with the noise falling in the range of 0.08 to 0.1 OD450units. The values are reported as IC50s, uM concentration.

On day 1, grow A431•FAKwt in T175 flasks. On the day prior to runningthe FAK cell-assay, seed A431•FAKwt cells in growth media on 96-wellU-bottom plates. Allow cells to sit at 37° C., 5% CO2 for 6 to 8 hoursprior to FAK induction. Prepare Mifepristone stock solution of 10 uM in100% Ethanol. The stock solution is subsequently diluted to 10× of thefinal concentration in Growth Media. Transfer 10 ul of this dilution(final concentration of 0.1 nM Mifepristone) into each well. Allow cellsto sit at 37° C., 5% CO2 overnight (12 to 16 hours). Also, preparecontrol wells without Mifepristone induction of FAK expression andphosphorylation.

On day 2, coat Goat Anti-Rabbit plate(s) with 3.5 ug/ml ofphosphospecific FAKpY397 polyclonal antibody prepared in SuperBlock TBSbuffer, and allow plate(s) to shake on a plate shaker at roomtemperature for 2 hours. Optionally, control wells may be coated with3.5 ug/ml of control Capture antibody (Whole Rabbit IgG molecules)prepared in SuperBlock TBS. Wash off excess FAKpY397 antibody 3 timesusing buffer. Block Anti-FAKpY397 coated plate(s) with 200 ul per wellof 3% BSA/0.5% Tween Blocking buffer for 1 hour at room temperature onthe plate shaker. While the plate(s) are blocking, prepare compoundstock solutions of 5 mM in 100% DMSO. The stock solutions aresubsequently serially diluted to 100× of the final concentration in 100%DMSO. Make a 1:10 dilution using the 100× solution into growth media andtransfer 10 ul of the appropriate compound dilutions to each wellcontaining either the FAK induced or uninduced control A431 cells for 30minutes at 37° C., 5% CO2. Prepare RIPA lysis buffer (50 mM Tris-HCl,pH7.4, 1% NP-40, 0.25% Na-deoxycholate, 150 mM NaCl, 1 mM EDTA, 1 mMNa3VO4, 1 mM NaF, and one Complete™ EDTA-free protease inhibitor pelletper 50 ml solution). At the end of 30 minutes compound treatment, washoff compound 3 times using TBS-T wash buffer. Lyse cells with 100ul/well of RIPA buffer.

To the coated plate, remove blocking buffer and wash 3 times using TBS-Twash buffer. Using a 96-well automated microdispenser, transfer 100 ulof whole cell-lysate (from step 6) to the Goat Anti-Rabbit FAKpY397coated plate(s) to capture phosphoFAKY397 proteins. Shake at roomtemperature for 2 hours. Wash off unbound proteins 3 times using TBS-Twash buffer. Prepare 0.5 ug/ml (1:2000 dilution) of UBI αFAK detectionantibody in 3% BSA/0.5% Tween blocking buffer. Dispense 100 ul of UBIαFAK solution per well and shake for 30 minutes at room temperature.Wash off excess UBI αFAK antibody 3 times using TBS-T wash buffer.Prepare 0.08 ug/ml (1:5000 dilution) of secondary Anti-Mouse Peroxidase(Anti-2MHRP) conjugated antibody. Dispense 100 ul per well of the Anti-2MHRP solution and shake for 30 minutes at room temperature. Wash offexcess Anti-2 MHRP antibody 3 times using TBS-T wash buffer. Add 100 ulper well of room temperature TMB substrate solution to allow for colordevelopment. Terminate the TMB reaction with 100 ul per well of TMB stopsolution (0.09M H2SO4) and quantitate the signal by measurement ofabsorbance at 450 nm on the BioRad microplate reader.

Additional FAK cell assays are hereby incorporated by reference fromPfizer Attorney Docket No. PC11699 entitled “INDUCIBLE FOCAL ADHESIONKINASE CELL ASSAY”.

In a preferred embodiment, the compounds of the present invention havean in vitro activity as determined by a kinase assay, e.g., such as thatdescribed herein, of less than 500 nM. Preferably, the compounds have anIC₅₀ of less than 25 nM in the kinase assay, and more preferably lessthan 10 nM. In a further preferred embodiment, the compounds exhibit anIC₅₀ in a FAK cell based assay, e.g., such as that described herein, ofless than 1 μM, more preferably less than 100 nM, and most preferablyless than 25 nM.

Still further, the following assay(s) may be used to assess the abilityof a compound of the present invention to inhibit osteoporosis and/orlow bone mass, as described above.

(1) Effect of Test Compound on Body Weight, Body Composition and BoneDensity in the Aged Intact and Ovariectomized Female Rat

This assay may be used to test the effects of a test compound in agedintact or ovariectomized (OVX) female rat model.

Study Protocol

Sprague-Dawley female rats are sham-operated or OVX at 18 months of age,while a group of rats is necropsied at day 0 to serve as baselinecontrols. One day post-surgery, the rats are treated with either vehicleor test compound. The vehicle or test compound is administered twice aweek (Tuesday and Friday) by subcutaneous injection (s.c.), with thetest compound being administered at an average dose of 10 milligrams perkilogram of body weight per day (10 mg/kg/day).

All rats are given s.c. injection of 10 mg/kg of calcein (Sigma, St.Louis, Mo.) for fluorescent bone label 2 and 12 days before necropsy. Onthe day of necropsy, all rats under ketamine/xylazine anesthesia areweighed and undergoe dual-energy X-ray absorptiometry (DXA, QDR-4500/W,Hologic Inc., Waltham, Mass.) equipped with Rat Whole Body Scan softwarefor lean and fat body mass determination. The rats are necropsied, thenautopsied and blood is obtained by cardiac puncture. The distal femoralmetaphysis and femoral shafts from each rat are analyzed by peripheralquantitative computerized tomography (pQCT), and volumetric total,trabecular and cortical bone mineral content and density are determined.

Peripheral Quantitative Computerized Tomography (pQCT) Analysis: Excisedfemurs are scanned by a pQCT X-ray machine (Stratec XCT Research M,Norland Medical Systems, Fort Atkinson, Wis.) with software version5.40. A 1 millimeter (mm) thick cross section of the femur metaphysis istaken at 5.0 mm (proximal femoral metaphysis, a primary cancellous bonesite) and 13 mm (femoral shafts, a cortical bone site) proximal from thedistal end with a voxel size of 0.10 mm. Cortical bone is defined andanalyzed using contour mode 2 and cortical mode 4. An outer thresholdsetting of 340 mg/cm³ is used to distinguish the cortical shell fromsoft tissue and an inner threshold of 529 mg/cm³ to distinguish corticalbone along the endocortical surface. Trabecular bone is determined usingpeel mode 4 with a threshold of 655 mg/cm³ to distinguish (sub)corticalfrom cancellous bone. An additional concentric peel of 1% of the definedcancellous bone is used to ensure that (sub)cortical bone is eliminatedfrom the analysis. Volumetric content, density, and area are determinedfor both trabecular and cortical bone (Jamsa T. et al., Bone 23:155–161,1998; Ke, H. Z. et al., Journal of Bone and Mineral Research,16:765–773, 2001).

Vaginal histology: Vaginal tissue is fixed and embedded in paraffin.Five micron sections are cut and stained with Alcian Blue staining.Histology examination of vaginal luminal epithelial thickness andmucopolysaccharide (secreted cells) is performed.

The experimental groups for the protocol are as follows:

-   -   Group I: Baseline controls    -   Group II: Sham+Vehicle    -   Group III: OVX+Vehicle    -   Group IV: OVX+Test Compound at 10 mg/kg/day (in Vehicle)        (2) Fracture Healing Assays

(a) Assay For Effects On Fracture Healing After Systemic Administration

Fracture Technique: Sprage-Dawley rats at 3 months of age areanesthetized with Ketamine. A 1 cm incision is made on the anteromedialaspect of the proximal part of the right tibia or femur. The followingdescribes the tibial surgical technique. The incision is carried throughto the bone, and a 1 mm hole is drilled 4 mm proximal to the distalaspect of the tibial tuberosity 2 mm medial to the anterior ridge.Intramedullary nailing is performed with a 0.8 mm stainless steel tube(maximum load 36.3 N, maximum stiffness 61.8 N/mm, tested under the sameconditions as the bones). No reaming of the medullary canal isperformed. A standardized closed fracture is produced 2 mm above thetibiofibular junction by three-point bending using specially designedadjustable forceps with blunt jaws. To minimize soft tissue damage, careis taken not to displace the fracture. The skin is closed withmonofilament nylon sutures. The operation is performed under sterileconditions. Radiographs of all fractures are taken immediately afternailing, and rats with fractures outside the specified diaphyseal areaor with displaced nails are excluded. The remaining animals are dividedrandomly into the following groups with 10–12 animals per each subgroupper time point for testing the fracture healing. The first groupreceives daily gavage of vehicle (water: 100% Ethanol=95:5) at 1 ml/rat,while the others receive daily gavage from 0.01 to 100 mg/kg/day of thecompound to be tested (1 ml/rat) for 10, 20, 40 and 80 days.

At 10, 20, 40 and 80 days, 10–12 rats from each group are anesthetizedwith Ketamine and sacrificed by exsanguination. Both tibiofibular bonesare removed by dissection and all soft tissue is stripped. Bones from5–6 rats for each group are stored in 70% ethanol for histologicalanalysis, and bones from another 5–6 rats for each group are stored in abuffered Ringer's solution (+4° C., pH 7.4) for radiographs andbiomechanical testing which is performed.

Histological Analysis: The methods for histologic analysis of fracturedbone have been previously published by Mosekilde and Bak (The Effects ofGrowth Hormone on Fracture Healing in Rats: A Histological Description.Bone, 14:19–27, 1993). Briefly, the fracture site is sawed 8 mm to eachside of the fracture line, embedded undecalcified in methymethacrylate,and cut frontals sections on a Reichert-Jung Polycut microtome in 8 μmthick. Masson-Trichrome stained mid-frontal sections (including bothtibia and fibula) are used for visualization of the cellullar and tissueresponse to fracture healing with and without treatment. Sirius redstained sections are used to demonstrate the characteristics of thecallus structure and to differentiate between woven bone and lamellarbone at the fracture site. The following measurements are performed: (1)fracture gap—measured as the shortest distance between the cortical boneends in the fracture, (2) callus length and callus diameter, (3) totalbone volume area of callus, (4) bony tissue per tissue area inside thecallus area, (5) fibrous tissue in the callus, and (6) cartilage area inthe callus.

Biomechanical Analysis: The methods for biomechanical analysis have beenpreviously published by Bak and Andreassen (The Effects of Aging onFracture Healing in Rats. Calcif Tissue Int 45:292–297, 1989). Briefly,radiographs of all fractures are taken prior to the biomechanical test.The mechanical properties of the healing fractures are analyzed by adestructive three- or four-point bending procedure. Maximum load,stiffness, energy at maximum load, deflection at maximum load, andmaximum stress are determined.

(b) Assay for Effects on Fracture Healing After Local Administration

Fracture Technique: Female or male beagle dogs at approximately 2 yearsof age are used under anesthesia in the study. Transverse radialfractures are produced by slow continuous loading in three-point bendingas described by Lenehan et al. (Lenehan, T. M.; Balligand, M.;Nunamaker, D. M.; Wood, F. E.: Effects of EHDP on Fracture Healing inDogs. J Orthop Res 3:499–507; 1985). A wire is pulled through thefracture site to ensure complete anatomical disruption of the bone.Thereafter, local delivery of prostaglandin agonists to the fracturesite is achieved by slow release of compound delivered by slow releasepellets or by administration of the compounds in a suitable formulationsuch as a paste gel solution or suspension for 10, 15, or 20 weeks.

Histological Analysis: The methods for histologic analysis of fracturedbone have been previously published by Peter et al. (Peter, C. P.; Cook,W. O.; Nunamaker, D. M.; Provost, M. T.; Seedor, J. G.; Rodan, G. A.Effects of alendronate on fracture healing and bone remodeling in dogs.J. Orthop. Res. 14:74–70, 1996) and Mosekilde and Bak (The Effects ofGrowth Hormone on Fracture Healing in Rats: A Histological Description.Bone, 14:19–27, 1993). Briefly, after sacrifice, the fracture site issawed 3 cm to each side of the fracture line, embedded undecalcified inmethymethacrylate, and cut on a Reichert-Jung Polycut microtome in 8 μmthick of frontal sections. Masson-Trichrome stained mid-frontal sections(including both tibia and fibula) are used for visualization of thecellullar and tissue response to fracture healing with and withouttreatment. Sirius red stained sections are used to demonstrate thecharacteristics of the callus structure and to differentiate betweenwoven bone and lamellar bone at the fracture site. The followingmeasurements are performed: (1) fracture gap—measured as the shortestdistance between the cortical bone ends in the fracture, (2) calluslength and callus diameter, (3) total bone volume area of callus, (4)bony tissue per tissue area inside the callus area, (5) fibrous tissuein the callus, (6) cartilage area in the callus.

Biomechanical Analysis: The methods for biomechanical analysis have beenpreviously published by Bak and Andreassen (The Effects of Aging onFracture Healing in Rats. Calcif Tissue Int 45:292–297, 1989) and Peteret al. (Peter, C. P.; Cook, W. O.; Nunamaker, D. M.; Provost, M. T.;Seedor, J. G.; Rodan, G. A. Effects of Alendronate On Fracture HealingAnd Bone Remodeling In Dogs. J. Orthop. Res. 14:74–70, 1996). Briefly,radiographs of all fractures are taken prior to the biomechanical test.The mechanical properties of the healing fractures are analyzed by adestructive three- or four-point bending procedures. Maximum load,stiffness, energy at maximum load, deflection at maximum load, andmaximum stress are determined.

Administration of the compounds of the present invention (hereinafterthe “active compound(s)”) can be effected by any method that enablesdelivery of the compounds to the site of action. These methods includeoral routes, intraduodenal routes, parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion),topical, and rectal administration.

The amount of the active compound administered will be dependent on thesubject being treated, the severity of the disorder or condition, therate of administration, the disposition of the compound and thediscretion of the prescribing physician. However, an effective dosage isin the range of about 0.001 to about 100 mg per kg body weight per day,preferably about 1 to about 35 mg/kg/day, in single or divided doses.For a 70 kg human, this would amount to about 0.05 to about 7 g/day,preferably about 0.2 to about 2.5 g/day. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day.

The active compound may be applied as a sole therapy or may involve oneor more other anti-tumour substances, for example those selected from,for example, mitotic inhibitors, for example vinblastine; alkylatingagents, for example cis-platin, carboplatin and cyclophosphamide;anti-metabolites, for example 5-fluorouracil, cytosine arabinoside andhydroxyurea, or, for example, one of the preferred anti-metabolitesdisclosed in European Patent Application No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; growth factor inhibitors; cell cycle inhibitors; intercalatingantibiotics, for example adriamycin and bleomycin; enzymes, for exampleinterferon; and anti-hormones, for example anti-estrogens such asNolvadex□ (tamoxifen) or, for example anti-androgens such as Casodex□(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution, suspension, for parenteral injection asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionwill include a conventional pharmaceutical carrier or excipient and acompound according to the invention as an active ingredient. Inaddition, it may include other medicinal or pharmaceutical agents,carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefor,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

Methods of preparing various pharmaceutical compositions with a specificamount of active compound are known, or will be apparent, to thoseskilled in this art. For examples, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

Where HPLC chromatography is referred to in the preparations andexamples below, the general conditions used, unless otherwise indicated,are as follows. The column used is a ZORBAX™ RXC18 column (manufacturedby Hewlett Packard) of 150 mm distance and 4.6 mm interior diameter. Thesamples are run on a Hewlett Packard-1100 system. A gradient solventmethod is used running 100 percent ammonium acetate/acetic acid buffer(0.2 M) to 100 percent acetonitrile over 10 minutes. The system thenproceeds on a wash cycle with 100 percent acetonitrile for 1.5 minutesand then 100 percent buffer solution for 3 minutes. The flow rate overthis period is a constant 3 mL/minute.

EXAMPLES

General Methods:

Preparation of 2,4-dichloro-5-trifluoromethylpyrimidine (3):

5-Trifluoromethyluracil (250 g, 1.39 mol) and phosphorous oxychloride(655 mL, 6.94 mol, 5 equiv) were charged to a 3 L 4-neck flask equippedwith overhead stirrer, a reflux condenser, an addition funnel and aninternal theromocouple. The contents were maintained under a nitrogenatmosphere as concentrated phosphoric acid (85 wt %, 9.5 mL, 0.1 equiv)was added in one portion to the slurry, resulting in a moderateexotherm. Diisopropylethylamine (245 mL, 1.39 mol, 1 equiv) was thenadded dropwise over 15 min at such a rate that the internal temperatureof the reaction reached 85–90° C. by the end of the addition. By the endof the amine addition the reaction mixture was a homogenous light-orangesolution. Heating was initiated and the orange solution was maintainedat 100° C. for 20 h, at which time HPLC analysis of the reaction mixtureindicated that the starting material was consumed. External heating wasremoved and the contents of the flask were cooled to 40° C. and thenadded dropwise to a cooled mixture of 3N HCl (5 L, 10 equiv) and diethylether (2 L) keeping the temperature of the quench pot between 10 and 15°C. The layers were separated, and the aqueous layer was extracted oncewith ether (1 L). The combined organic layers were combined, washed withwater until the washes were neutral (5×1.5 L washes), dried with MgSO₄and concentrated to provide 288 g (95% yield) of a light yellow-orangeoil of 96% purity (HPLC). This material can be further purified bydistillation (bp 109° C. at 79 mmHg).

Preparation of 4-Amino-1,3-dihydro-indol-2-one:

Dimethylmalonate (13.70 g, 2.1 eq) was added dropwise to a suspension ofsodium hydride (4.94 g, 2.5 eq) in DMSO (150 mL) at 0° C. This mixturewas then heated to 100° C. for 1 hour, cooled to RT, then2-chloro-1,3-dinitrobenzene (10 g, 49.3 mmol) was added and the reactionheated to 100° C. for 3 hours. The reaction was cooled to RT andquenched with sat. NH₄Cl, extracted with ether and dried over Na₂SO₄ andconcentrated to give 10.35 g (70%) of a white solid. The resulting solid(8.33 g) was dissolved in acetic acid (30 mL) and p-toluensulfonic acid(250 mg) added followed by heating to reflux for 3 hours. The hotreaction was poured into water and solids crashed out and were filtered,5.7 g (85%). The solid material was then dissolved in ethanol, Pd/C (400mg) added and the solution hydrogenated at 40 psi H₂ overnight. Afterfiltering through celite to remove Pd, solution was heated withp-toluensulfonic acid (200 mg) at reflux for 2 hours. The reaction wasthen concentrated and the product crystallized and was filtered to givea brown solid, 2.75 g (74%). 1H NMR (DMSO-d₆, 400 MHz) δ 3.12 (s, 2H),5.02 (br s, 2H), 6.02 (d, J=7.5 Hz, 1H), 6.18 (d, J=7.9 Hz; 1H), 6.80(t, J=7.9 Hz, 1H), 10.09 (s, 1H); HPLC ret. time: 2.317 min. LRMS (M+)148.8.

4-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one:

4-amino-oxindole (2.75 g, 18.6 mmol) was added portionwise to a solutionof 5-trifluoromethyl-2,4-dichloropyrimidine (4.03 g, 1 eq) and ZnCl₂(18.6 mL of a 1M solution in ether) in 1:1 DCE/t-butanol (60 mL) at 0°C. After 15 minutes a solution of Et₃N (2.85 mL, 1.1 eq) in 1:1DCE/t-butanol (20 mL) was added dropwise. The reaction was allowed towarm to RT overnight. The reaction was then concentrated and the producttriturated from methanol as a grey solid 3.05 g (50%). 1H NMR (DMSO-d₆,400 MHz) δ 3.43 (s, 2H), 6.64 (m, 1H), 7.14 (m, 2H), 8.74 (s, 1H), 10.32(s, 1H), 10.43 (s, 1H); HPLC ret. time: 5.859 min. LRMS (M+) 329.1,331.0.

Preparation of 6-Amino-1,3-dihydro-indol-2-one: 2,4-dinitrophenylaceticacic (10 g; 44 mmol) was dissolved in ethanol (200 mL) and purged withN₂. 10% Pd/C (400 mg) was added and the reaction hydrogenated at 45 psifor 2 hours. The reacton was then transferred to a RBF andp-toluenesulfonic acid (150 mg) was added and the reaction heated atreflux overnight. The reaction was then filtered through celite toremove catalyst and concentrated. The product crashed out and wasfiltered as tan crystals 4.68 g (72% yield). 1H NMR (DMSO-d₆, 400 MHz) δ3.20 (s, 2H), 4.97 (br s, 2H), 6.07 (m, 2H), 6.76 (d, J=8.7 Hz; 1H),10.05 (s, 1H); HPLC ret. time: 2.123 min. LRMS (M+) 148.7.

Preparation of6-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one:To a solution of 2,4-dichloro-5-trifluoromethylpyrimidine (3.51 g; 16.2mmol) in THF (100 mL) was added a solution of ZnCl₂ (1M in ether; 16.2mL). After 15 minutes 6-aminooxindole (2 g; 13.5 mmol) was added insmall portions, followed by the dropwise addition of Et₃N (1.63 g; 16.2mmol) in 10 mL of THF. The reaction was then stirred at RT overnight.Following removal of the solvent under reduced pressure, the crudereaction was triturated from methanol and the product filtered off as ayellow solid 2.2 g (50% yield). 1H NMR (DMSO-d₆, 400 MHz) δ 3.40 (s,2H), 7.13 (d, J=8.3 Hz, 2H), 7.20 (d, J=7.9 Hz; 1H), 7.27 (br s, 1H),8.75 (s, 1H), 10.41 (s, 1H), 10.62 (s, 1H); HPLC ret. time: 5.933 min.LRMS (M+) 329.1, 331.0.

Preparation of 7-Amino-1,3-dihydro-indol-2-one:

Hydrogen peroxide (20 ml) was added to a solution of 7-nitroquinoline(10 g, 57.4 mmol) in acetic acid (40 mL) and heated to 70° C. for 4hours. Then an additional 20 mL of H₂O₂ was added and the reactionheated to 70° C. for an additional 4 hours. Upon cooling an orange solidformed and was filtered. The solid was dissolved in ethanol, Pd/C (150mg) was added and the solution hydrogenated at 40 psi H₂ overnight.After filtering through celite to remove Pd, the reaction was thenconcentrated and the product crystallized from methanol as a greensolid, 697 mg (14%). 1H NMR (DMSO-d₆, 400 MHz) δ 3.36 (s, 2H), 4.78 (brs, 2H), 6.44 (m, 2H), 6.65 (t, J=7.5 Hz; 1H), 9.86 (s, 1H); HPLC ret.time: 2.807 min. LRMS (M+) 148.8.

Preparatin of7-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one:

7-amino-oxindole (910 mg, 6.1 mmol) was added portionwise to a solutionof 5-trifluoromethyl-2,4-dichloropyrimidine (1.33 g, 1 eq) and ZnCl₂(6.1 mL of a 1M solution in ether) in 1:1 DCE/t-butanol (30 mL) at 0° C.After 15 minutes a solution of Et₃N (0.94 mL, 1.1 eq) in 1:1DCE/t-butanol (10 mL) was added dropwise. The reaction was allowed towarm to RT overnight. The reaction was then concentrated and the producttriturated from methanol as a green solid 1.61 g (81%). 1H NMR (DMSO-d₆,400 MHz) δ 3.51 (s, 2H), 6.92 (m, 1H), 7.08 (d, J=7.5 Hz, 2H), 8.66 (s,1H), 10.10 (s, 1H), 10.17 (s, 1H); HPLC ret. time: 5.870 min. LRMS (M+)329.1, 331.1.

Preparation of 5-Amino-3,3-difluoro-1,3-dihydro-indol-2-one:

A 1.00 g (5.20 mmol) aliquot of 5-nitroisatin was suspended in 52.0 mLdry dichloromethane. 1.51 mL (11.5 mmol) DAST (N,N-DiethylaminosulfurTrifluoride) was very carefully added under an atmosphere of nitrogen.The reaction mixture was allowed to stir at ambient temperature for fourdays (out of convenience as progression of the reaction halted afteronly one). The reaction was chilled to 0° C. in an ice bath. Excess DASTwas carefully quenched through the addition of 5.0 mL methanol. Afteraddition of the methanol, a complete solution was observed. This brownreaction solution was washed with 50.0 mL water, and the aqueous wasextracted with dichloromethane. The combined organics were dried oversodium sulfate and evaporated under reduced pressure to give a brownsolid. This solid was purified over silica gel (dichloromethane aseluent) to give 3,3-Difluoro-5-nitro-1,3-dihydro-indol-2-one as ayellow-orange solid in 51% yield (578 mg, 2.70 mmol). The resultingsolid (280 mg) was taken into 7.00 mL tetrahydrofuran and 28.0 mL ethylacetate. this was added 91 μL (0.524 mmol) diisopropylethylamine and 139mg (0.131 mmol) palladium on carbon (10%). The reaction mixture wassubjected to 40 parts per square inch hydrogen pressure on a parr shakerapparatus for one-and-a-half hours. The reaction was removed fromhydrogen pressure and filtered through a bed of diatomaceous earth. Thefiltrate was concentracted under reduced pressure to give the titledcompound in quantitative yield as a brown solid. GC/MS r.t.=3.38 min.,m/z 184 (bp, MI), 156, 129, 105; ¹H NMR (D₆-DMSO) δ 10.67 (s, 1 H), 6.77(s, 1 H), 6.65 (bs, 1 H), 6.64 (bs, 1 H), 5.10 (s, 2H) ppm.

Preparation of5-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3,3-difluoro-1,3-dihydro-indol-2-one:

316 mg (1.46 mmol) 5-trifluoromethyl-2,4-dichloropyrimidine was takeninto 2.30 mL of a 1:1 mix of tert-butanol and 1,2-dichloroethane. Tothis solution was added 1.46 mL (1.46 mmol) zinc chloride solution (1.0M in ether). The reaction solution was allowed to stir at ambienttemperature for thirty minutes. 1.31 mmol5-Amino-3,3-difluoro-1,3-dihydro-indol-2-one was added drop-wise as asuspension in 500 □L tert-butanol/1,2-dichloroethane solvent mixture.202 □L (1.46 mmol) triethylamine was slowly added to the slurry. Aslight exotherm and severe clumping was noted (Too much diethyl ether toallow for solution). Allowed the reaction mixture to stir at ambienttemperature overnight (16 hours). A complete solution had been achievedover the period. All volatiles were removed under reduced pressure toreveal a brown foam. Triteration from methanol gave the titled compoundas a tan solid upon filtration in 31% yield (164 mg, 0.450 mmol). APCIm/z 365.2/367.2 (MH⁺); ¹H NMR (D₆-DMSO) δ 11.17 (s, 1 exchangeable H),10.73 (s, 1 exchangeable H), 8.80 (bs, 1 H), 8.00 (bs, 1 H), 7.69 (d,J=8.3 Hz, 1H), 6.99 (d, J=8.3 Hz, 1 H) ppm.

Preparation of 5-Amino-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one:

340 mg (2.08 mmol) 5-Nitro-1H-pyrrolo[2,3-b]pyridine was taken into 6.00mL 1:1 tert-butanol/water mixture and cooled to 0° C. To this was slowlyadded 322 μL (6.25 mmol) molecular bromine. The reaction was allowed toslowly warm to ambient temperature over sixteen hours. The volatilesfrom the reaction mixture were removed under reduced pressure and theremaining aqueous residue was chilled to 0° C. The pH was adjusted toapproximately 9.0 using a saturated sodium bicarbonate solution.Filtration of the resulting brown-orange solid afforded the3,3-dibromo-oxindole intermediate in a nearly quantitative yield (¹H NMR(CD₃OD) δ 9.10 (s, 1 H), 8.70 (s, 1 H) ppm.) The dibromooxindoleintermediate obtained above was dissolved in 50 mL ethanol. 34 mg 10%palladium on activated carbon was carefully added and the reaction wassubjected to 45 parts per square inch hydrogen pressure on a parr shakerapparatus for two hours. The reaction was removed from the hydrogenatmosphere and filtered through a bed of diatomaceous earth. Thevolatiles from the filtrate were removed under reduced pressure to givethe titled compound in a 79% yield as an off-white solid (245 mg, 1.64mmol). GC/MS r.t.=3.51 min., m/z 149 (MI, bp), 121, 94; ¹H NMR (D₆-DMSO)δ 11.22 (bs, 1 H), 8.04 (s, 1 H), 7.54 (s, 1 H), 3.61 (s, 2 H) ppm.

Preparation of5-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-Pyrrolo[2,3-b]pyridin-2-one:

211 mg (0.972 mmol) 5-trifluoromethyl-2,4-dichloropyrimidine was takeninto 1.00 mL 1:1 tert-butanol:1,2-dichloroethane mixture. To this wasadded 972 mL (0.972 mmol) zinc chloride solution. 145 mg (0.972 mmol)5-Amino-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one was taken into 500 mLtert-butanol/1,2-dichloroethane mix with 169 mL (0.972 mmol)diisopropylethylamine and 2.92 mL (2.92 mmol) zinc chloride solution.Allowed both solutions stir at ambient temperature for thirty minutes.The oxindole-bearing solution was slowly added drop-wise to the solutioncontaining the trifluoromethylpyrimidine. Allowed the combined solutionsto stir at ambient temperature for sixteen hours. The volatiles from thereaction mixture were removed under reduced pressure. The resultingglass was taken up into 10% methanol in dichloromethane and washedthoroughly with 1 N sodium hydroxide. Organic layer was dried overmagnesium sulfate and evaporated under reduced pressure to give a yellowsolid. The titled compound was obtained through purification of thisyellow solid over silica (97.8:2:0.2 CHCl₃:CH₃OH:NH₄OH) as a yellowsolid in a 13% yield (43 mg, 0.130 mmol). APCI m/z 330.0/331.9 (MH⁺), ¹HNMR (D₆-DMSO) δ 10.96 (s, 1 H), 10.57 (s, 1 H), 8.74 (s, 1 H), 8.23 (s,1 H), 7.85 (s, 1 H), 3.56 (s, 2 H) ppm.

Example 1

4-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one:3-methanesulfonyl-benzylamine mono-acetate (150 mg, 0.61 mmol) and4-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one(200 mg, 1 eq) were combined with Et₃N (136 mg, 2.2 eq) in dioxane (3mL) at 100° C. for 3 hours. The reaction was cooled to RT and productcrystallized by the addition of water to the crude reaction. The productwas filtered of as a tan solid, 139 mg (48%). 1H NMR (DMSO-d₆, 400 MHz)δ 3.11 (s, 3H), 3.39 (s, 2H), 4.62 (d, J=5.8 Hz, 2H), 6.48 (d, J=7.5 Hz,1H), 6.96 (m, 1H), 7.07 (d, J=8.3 Hz, 1H), 7.53 (m, 2H), 7.75 (d, J=7.5Hz, 1H), 7.83 (m, 2H), 8.19 (s, 1H), 9.08 (s, 1H), 10.31 (s, 1H); HPLCret. time: 5.314 min. LRMS (M+) 478.2.

The following compounds of the invention may be prepared by the methodoutlined in Example 1; heating chloropyrimidine (4) with an appropriateamine. Amines used in these reactions were either obtained commerciallyand used as received or alternatively they were prepared by commonsynthetic methods for amines known to those skilled in the art. Unlessotherwise noted, compounds having chiral centers were prepared asracemic mixtures.

TABLE 1 HPLC ret time LRMS Name (min) MH+6-{4-[(1-Methanesulfonyl-piperidin-3-ylmethyl)- 5.37 485.3amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3- dihydro-indol-2-one6-[4-(3-Methanesulfonyl-benzylamino)-5- 5.31 478.1trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one6-[4-(3-Methanesulfonyl-benzylamino)-5- 5.31 478.1trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-oneMethanesulfonic acid 3-{[2-(2-oxo-2,3-dihydro-1H- 5.86 494.1indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4- ylamino]-methyl}-phenylester 6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2- 6.28 364.2ylamino)-1,3-dihydro-indol-2-oneN-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-6- 5.69 507.2ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Methyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-6- 6.01 507.1ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-(5-Methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6- 507.1ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Methyl-N-(4-methyl-3-{[2-(2-oxo-2,3-dihydro-1H- 521.1indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-(4-Fluoro-3-{[2-(2-oxo-2,3-dihydro-1H-indol-6- 525.1ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-#N!-methyl-methanesulfonamideN-Methyl-N-(3-methyl-2-{[2-(2-oxo-2,3-dihydro-1H- 521.1indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-(4-Methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-6- 507.1ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Methyl-N-(4-methyl-2-{[2-(2-oxo-2,3-dihydro-1H- 521.1indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-(3-Methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6- 507.1ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Methyl-N-(2-methyl-6-{[2-(2-oxo-2,3-dihydro-1H- 521.1indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-(4-Fluoro-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6- 525.1ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamideN-(3-Fluoro-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6- 525.1ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamideN-Methyl-N-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H- 521.1indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Methyl-N-(4-{[2-(2-oxo-2,3-dihydro-1H-indol-6- 508.1ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-{1,1-Dimethyl-3-[2-(2-oxo-2,3-dihydro-1H-indol-6- 473.1ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamideN-(4-Methoxy-3-{[2-(2-oxo-2,3-dihydro-1H-indol-6- 523.1ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide6-(4-{[(5-Fluoro-2-trifluoromethyl-phenyl)methyl]- 486.1amino}-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3- dihydro-indol-2-one6-(4-Cyclopentylamino-5-trifluoromethyl-pyrimidin-2- 378.1ylamino)-1,3-dihydro-indol-2-oneN-(4,6-Dimethyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol- 536.16-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-N-methyl-methanesulfonamideN-{2-[2-(2-Oxo-2,3-dihydro-1H-indol-6-ylamino)-5- 431.1trifluoromethyl-pyrimidin-4-ylamino]-ethyl}- methanesulfonamide6-(4-{[(3,5-Dimethoxy-phenyl)methyl]-amino}-5- 460.1trifluoromethyl-pyrimidin-2-ylamino)-1,3- dihydro-indol-2-one6-[5-Trifluoromethyl-4-(2-trifluoromethyl- 468.1benzylamino)-pyrimidin-2-ylamino]- 1,3-dihydro-indol-2-one3,3-Difluoro-5-[4-(3-methanesulfonyl-benzylamino)-5- 6.15 514.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-oneN-(3-{[2-(3,3-Difluoro-2-oxo-2,3-dihydro-1H-indol-5- 6.45 543.3ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide5-[4-(3-Methanesulfonyl-benzylamino)-5- 4.83 479.2trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and theaccompanying figures. Such modifications are intended to fall within thescope of the appended claims.

All patents, applications, publications, test methods, literature, andother materials cited herein are hereby incorporated herein by referencein their entireties.

1. A compound of the formula 1

or a pharmaceutically acceptable salt thereof, wherein Ar is selectedfrom:

and ring B is

wherein m is an integer from 0–2, Ra is a substituent attached to anyaromatic carbon capable of substitution, wherein Ra is selected from thegroup consisting of hydrogen, halogen, hydroxy, —CF₃, —CN,—(C₁–C₆)alkyl, —NR⁵R⁶, —OR¹², —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl,—CO₂R¹², —CONR⁵R⁶ and —CONR⁵R⁸; Rb is a substituent selected from thegroup consisting of hydrogen, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —CO₂R¹², and —CONR⁵R⁶; each Rc independentlyrepresents a substituent selected from the group consisting of hydrogen,halogen, hydroxy, —CF₃, —CN, —(C₁–C₆)alkyl, —NR⁵R⁶, —OR¹²,—(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —CO₂R¹², —CONR⁵R⁶ and—CONR⁵R⁸; or two Rc substituents may be taken together with the carbonatom to which they are attached to form a cyclic group selected from thegroup consisting of —(C₃–C₁₀)-cycloalkyl and —(C₂–C₉)-heterocyclyl; withthe proviso that Ar cannot be

wherein n is an integer from 1 to 3; each R¹ is a substituentindependently selected from the group consisting of hydrogen, hydroxy,—(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —O(C₁–C₆)alkyl,—O(C₃–C₇)cycloalkyl, —O(C₂–C₉)heterocyclyl, —NR⁵R⁶, —SR⁷, —SOR⁷, —SO₂R⁷,—CO₂R¹², —CONR⁵R⁶, —SO₂NR⁵R⁶, —NHCOR¹², —NR¹²CONR⁵R⁶, and —NR¹²SO₂R⁷;wherein said R¹ substituents, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —O(C₁–C₆)alkyl, —O(C₃–C₇)cycloalkyl,—O(C₂–C₉)heterocyclyl, —NR⁵R⁶, —SR⁷, —SOR⁷, —SO₂R⁷, —CO₂R¹², —CONR⁵R⁶,—SO₂NR⁵R⁶, —NHCOR¹², —NR¹²CONR⁵R⁶, and —NR¹²SO₂R⁷, are optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CF₃, —CN,—(C₁–C₆)alkyl, —NR⁵R⁶, —OR¹², —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl,—CO₂R¹², —CONR⁵R⁶ and —CONR⁵R⁸; each R² is a substituent independentlyselected from the group consisting of hydrogen, —(C₁–C₆)alkyl,—(C₂–C₆)alkenyl, —(C₂–C₆)alkynyl, —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —CO₂R¹², and —CONR⁵R⁶; wherein said R²substituents, —(C₁–C₆)alkyl, —(C₂–C₆)alkenyl, —(C₂–C₆)alkynyl,—(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —CO₂R¹², and —CONR⁵R⁶, areoptionally substituted by one to three moieties independently selectedfrom the group consisting of hydrogen, halogen, hydroxy, —CF₃, —NO₂,—CN, —(C₁–C₆)alkyl, —(C₂–C₆)alkenyl, —(C₂–C₆)alkynyl, —C═N—OH,—C═N—O((C₁–C₆)alkyl), —NR⁵R⁶, —OR¹², —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —CO₂R¹², —CONR⁵R⁶, —CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁵R⁶, —NHCOR¹², —NR¹²CONR⁵R⁶, and —NR¹²SO₂R⁷, wherein said—(C₂–C₆)alkenyl and —(C₂–C₆)alkynyl R² moieties may be optionallysubstituted by one to three R¹² groups; R¹ and R² may be taken togetherwith the atom(s) to which they are attached to form a cyclic group,—(C₃–C₁₀)cycloalkyl or —(C₂–C₉)heterocyclyl, wherein said cyclic groupis optionally substituted by one to three moieties independentlyselected from the group consisting of hydrogen, halogen, hydroxy, —CF₃,—NO₂, —CN, —(C₁–C₆)alkyl, —(C₂–C₆)alkenyl, —(C₂–C₆)alkynyl, —C═N—OH,—C═N—O((C₁–C₆)alkyl), —NR⁵R⁶, —OR¹², —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —CO₂R¹², —CONR⁵R⁶, —CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁵R⁶, —NHCOR¹², —NR¹²CONR⁵R⁶, and —NR¹²SO₂R⁷, wherein said—(C₂–C₆)alkenyl and —(C₂–C₆)alkynyl moieties of said cyclic group may beoptionally substituted by one to three R¹² groups, and said cyclic groupis optionally interrupted by one to three elements selected from thegroup consisting of —(C═O), —SO₂, —S—, —O—, —N—, —NH— and —NR¹²; R³ is asubstituent selected from the group consisting of: (a) hydrogen; (b)—(C₆–C₁₀)aryl or —(C₁–C₉)heteroaryl, optionally substituted by one tothree moieties independently selected from the group consisting ofhalogen, hydroxy, —(C₁–C₆)alkyl, —(C₁–C₆)alkyl-P(O)(O(C₁–C₆)alkyl)₂,—(C₃–C₁₀)cycloalkyl, (C₆–C₁₀)aryl, (C₂–C₉)heterocyclyl,—(C₁–C₉)heteroaryl, —NR⁵R⁶, —NHSO₂(C₁–C₆)alkyl, —NHSO₂(C₃–C₆)cycloalkyl,—N((C₁–C₆)alkyl)(SO₂—C₁–C₆)alkyl),—N((C₁–C₆)alkyl)(SO₂(C₃–C₆)cycloalkyl),—N((C₃–C₆)cycloalkyl)(SO₂—C₁–C₆)alkyl),—N((C₃–C₆)cycloalkyl)(SO₂(C₃–C₆)cycloalkyl), —O(C₁–C₆)alkyl,—O—SO₂(C₁–C₆)alkyl, —O—SO₂(C₃–C₆)cycloalkyl, —(CO)(C₁–C₆)alkyl,—(CO)CF₃, —(CO)(C₃–C₁₀)cycloalkyl, —(CO)(C₆–C₁₀)aryl,—(CO)(C₂–C₉)heterocyclyl, —(CO)(C₁–C₉)heteroaryl, —(CO)O(C₁–C₆)alkyl,—(CO)O(C₃–C₁₀)cycloalkyl, —(CO)O(C₆–C₁₀)aryl, —(CO)O(C₂–C₉)heterocyclyl,—(CO)O(C₁–C₉)heteroaryl, —(CO)(C₁–C₆)alkyl-O(C₁–C₆)alkyl,—SO₂(C₁–C₆)alkyl, —SO₂(C₃–C₆)cycloalkyl, SO₂CF₃, SO₂NH₂,SO₂NH(C₁–C₆)alkyl, —SO₂NH(C₃–C₆)cycloalkyl, —SO₂N((C₁–C₆)alkyl)₂,SO₂N((C₁–C₆)alkyl)((C₃–C₆)cycloalkyl), —SO₂N((C₃–C₆)cycloalkyl)₂ and—SO₂NR⁵R⁶, wherein said —(C₆–C₁₀) aryl or —(C₁–C₉) heteroaryl areoptionally interrupted by one to three elements selected from the groupconsisting of —S—, —O—, —N—, —NH— and —NR¹²; (c) —(C₃–C₁₀)cycloalkyl,—(C₂–C₉)heterocyclyl, and —(C₁–C₆)alkyl-(C₂–C₉) heterocyclyl, optionallysubstituted by one to three moieties independently selected from thegroup consisting of halogen, hydroxy, —(C₁–C₆)alkyl,—(C₁–C₆)alkyl-P(O)(O(C₁–C₆)alkyl)₂, —(C₃–C₁₀)cycloalkyl, (C₆–C₁₀)aryl,(C₂–C₉)heterocyclyl, —(C₁–C₉)heteroaryl, —NR⁵R⁶, —NSO₂(C₁–C₆)alkyl,—NHSO₂(C₃–C₆)cycloalkyl, —N((C₁–C₆)alkyl)(SO₂—C₁–C₆)alkyl),—N((C₁–C₆)alkyl)(SO₂(C₃–C₆)cycloalkyl),—N((C₃–C₆)cycloalkyl)(SO₂—C₁–C₆)alkyl),—N((C₃–C₆)cycloalkyl)(SO₂(C₃–C₆)cycloalkyl), —O(C₁–C₆)alkyl,—O—SO₂(C₁–C₆)alkyl, —O—SO₂(C₁–C₆)alkyl, —O—SO₂(C₃–C₆)cycloalkyl,—(CO)(C₁–C₆)alkyl, —(CO)CF₃, —(CO)(C₃–C₁₀)cycloalkyl, —(CO)(C₆–C₁₀)aryl,—(CO)(C₂–C₉)heterocyclyl, —(CO)(C₁–C₉)heteroaryl, —(CO)O(C₁–C₆)alkyl,—(CO)O(C₃–C₁₀)cycloalkyl, —(CO)O(C₆–C₁₀)aryl, —(CO)O(C₂–C₉)heterocyclyl,—(CO)O(C₁–C₉)heteroaryl, —(CO)(C₁–C₆)alkyl-O(C₁–C₆)alkyl,—SO₂(C₁–C₆)alkyl, —SO₂(C₃–C₆)cycloalkyl, SO₂CF₃, SO₂NH₂,SO₂NH(C₁–C₆)alkyl, —SO₂NH(C₃–C₆)cycloalkyl, —SO₂N((C₁–C₆)alkyl)₂,SO₂N((C₁–C₆)alkyl)((C₃–C₆)cycloalkyl), —SO₂N((C₃–C₆)cycloalkyl)₂ and—SO₂NR⁵R⁶; wherein said —(C₃–C₁₀)cycloalkyl, —(C₂–C₉)heterocyclyl, and—(C₁–C₆)alkyl-(C₂–C₉) heterocyclyl are optionally interrupted by one tothree elements selected from the group consisting of —(C═O), —SO₂, —S—,—O—, —N—, —NH— and —NR¹²; (d) —(C₁–C₆)alkyl optionally substituted byone to three moieties selected from the group consisting of halogen,hydroxy, —(C₁–C₆)alkyl, —(C₁–C₆)alkyl-P(O)(O(C₁–C₆)alkyl)₂,—(C₃–C₁₀)cycloalkyl, (C₆–C₁₀)aryl, (C₂–C₉)heterocyclyl,—(C₁–C₉)heteroaryl, —NR⁵R⁶, —NHSO₂(C₁–C₆)alkyl, —NHSO₂(C₃–C₆)cycloalkyl,—N((C₁–C₆)alkyl)(SO₂—C₁–C₆)alkyl),—N((C₁–C₆)alkyl)(SO₂(C₃–C₆)cycloalkyl),—N((C₃–C₆)cycloalkyl)(SO₂—C₁–C₆)alkyl),—N((C₃–C₆)cycloalkyl)(SO₂(C₃–C₆)cycloalkyl), —O(C₁–C₆)alkyl,—O—SO₂(C₁–C₆)alkyl, —O—SO₂(C₃–C₆)cycloalkyl, —(CO)(C₁–C₆)alkyl,—(CO)CF₃, —(CO)(C₃–C₁₀)cycloalkyl, —(CO)(C₆–C₁₀)aryl,—(CO)(C₂–C₉)heterocyclyl, —(CO)(C₁–C₉)heteroaryl, —(CO)O(C₁–C₆)alkyl,—(CO)O(C₃–C₁₀)cycloalkyl, —(CO)O(C₆–C₁₀)aryl, —(CO)O(C₂–C₉)heterocyclyl,—(CO)O(C₁–C₉)heteroaryl, —(CO)(C₁–C₆)alkyl-O(C₁–C₆)alkyl,—SO₂(C₁–C₆)alkyl, —SO₂(C₃–C₆)cycloalkyl, SO₂CF₃, SO₂NH₂,SO₂NH(C₁–C₆)alkyl, —SO₂NH(C₃–C₆)cycloalkyl, —SO₂N((C₁–C₆)alkyl)₂,SO₂N((C₁–C₆)alkyl)((C₃–C₆)cycloalkyl), —SO₂N((C₃–C₆)cycloalkyl)₂ and—SO₂NR⁵R⁶, wherein said —(C₁–C₆)alkyl is optionally interrupted by oneto three elements selected from the group consisting of —(C═O), —SO₂,—S—, —O—, —N—, —NH— and —NR¹²; and wherein each R³ (b)–(d) substituent,moiety, or element is optionally substituted by one to three radicalsindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CF₃, —NO₂, —CN, —(C₁–C₆)alkyl, —(C₂–C₆)alkenyl,—(C₂–C₆)alkynyl, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl,—(C₆–C₁₀)aryl, —(C₁–C₉)heteroaryl, —O(C₁–C₆)alkyl, —O(C₃–C₇)cycloalkyl,—O(C₂–C₉)heterocyclyl, —C═N—OH, —C═N—O(C₁–C₆ alkyl), —NR⁵R⁶, —SR⁷,—SOR⁷, —SO₂R⁷, —CO₂R¹², —CONR⁵R⁶, —SO₂NR⁵R⁶, —NHCOR⁵, —NR¹²CONR⁵R⁶, and—NR¹² SO₂R⁷; and wherein R⁵ and R⁶ of said —CONR⁵R⁶, —SO₂NR⁵R⁶, and—NR¹²CONR⁵R⁶ groups may be taken together with the atoms to which theyare attached to form a —(C₂–C₉)heterocyclyl; R⁴ is a substituentselected from the group consisting of hydrogen, (C₁–C₆)alkyl,—(C₃–C₇)cycloalkyl, and —(C₂–C₉)heterocyclyl; wherein said (C₁–C₆)alkyl,—(C₃–C₇)cycloalkyl, and —(C₂–C₉)heterocyclyl R⁴ substituents areoptionally substituted by one to three moieties independently selectedfrom the group consisting of hydrogen, halogen, hydroxyl, —(C₁–C₆)alkyl,—CN, —NR⁵R⁶, —OR⁵, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —CO₂R¹²,—SO₂NR⁵R⁶, NR¹²SO₂R⁷, —SO₂R⁷ and —CONR⁵R⁸; wherein R⁵ and R⁸ of said—CONR⁵R⁸ group may be taken together with the atoms to which they areattached to form a —(C₂–C₉)heterocyclyl; R⁵ and R⁶ are each substituentsindependently selected from the group consisting of hydrogen,—(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl,—(C₁–C₉)heteroaryl, COR¹² and —SO₂R¹²; wherein said —(C₁–C₆)alkyl,—(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl,—(C₁–C₉)heteroaryl, COR¹² and —SO₂R¹² R⁵ or R⁶ substituents areoptionally substituted by one to three moieties independently selectedfrom the group consisting of hydrogen, halogen, —CF₃, —CN,—(C₁–C₆)alkyl, —NH(C₁–C₆)alkyl, —NH(C₃–C₇)cycloalkyl,—NH(C₂–C₉)heterocyclyl, —NH(C₆–C₁₀)aryl, —NH(C₁–C₉)heteroaryl,—N((C₁–C₆)alkyl)₂, —N((C₃–C₇)cycloalkyl)₂, —N((C₂–C₉)heterocyclyl)₂,—N((C₆–C₁₀)aryl)₂, —N((C₁–C₉)heteroaryl)₂, —O(C₁–C₆)alkyl,—O(C₃–C₇)cycloalkyl, —O(C₂–C₉)heterocyclyl, —O(C₆–C₁₀)aryl,—O(C₁–C₉)heteroaryl, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —CO₂R⁷,SO₂NR⁵R⁶, NR¹²SO₂R⁷, —SO₂R^(7,)—CONH₂, —CONHR⁷, and —CONR⁷R⁸; wherein R⁷and R⁸ of said —CONR⁷R⁸ group may be taken together with the nitrogenatom to which they are attached to form a —(C₂–C₉) heterocyclyl; R⁵ andR⁶ may be taken together with the atom(s) to which they are attached toform a —(C₂–C₉)heterocyclyl, wherein said —(C₂–C₉)heterocyclyl group isoptionally substituted by one to three moieties selected from the groupconsisting of hydrogen, halogen, hydroxy, —CF₃, —NO₂, —CN,—(C₁–C₆)alkyl, —(C₂–C₆)alkenyl, —(C₂–C₆)alkynyl, —C═N—OH,—C═N—O((C₁–C₆)alkyl), —NR⁷R⁸, —OR¹², —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —CO₂R¹², —CONR⁷R⁸, —CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁷R⁸, —NHCOR¹², —NR¹²CONR⁷R⁸, and —NR¹²SO₂R⁷, wherein said—(C₂–C₆)alkenyl and —(C₂–C₆)alkynyl moieties of said—(C₂–C₉)heterocyclyl group may be optionally substituted by one to threeR⁷ groups, and said —(C₂–C₉)heterocyclyl group is optionally interruptedby one to three elements selected from the group consisting of —(C═O),—SO₂, —S—, —O—, —N—, —NH— and —NR¹²; R⁷ is a substituent selected fromthe group consisting of —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl, and —(C₁–C₉) heteroaryl; whereinsaid —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl,—(C₆–C₁₀)aryl, and —(C₁–C₉) heteroaryl R⁷ substituents are optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁–C₆)alkyl,—NR¹² ₂, and —O(C₁–C₆)alkyl; R⁸ is a substituent selected from the groupconsisting of hydrogen, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl, and —(C₁–C₉) heteroaryl; whereinsaid —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl,—(C₆–C₁₀)aryl, and —(C₁–C₉) heteroaryl R⁸ radicals are optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁–C₆)alkyl,—NH₂, —NHR⁹, —NR⁹ ₂, OR⁹, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl,—CO₂R¹⁰, —CONH₂, —CONHR¹⁰, and —CONR¹⁰R¹¹; wherein R¹⁰ and R¹¹ of—CONR¹⁰R¹¹ may be taken together with the nitrogen atom to which theyare attached to form a —(C₂–C₉)heterocyclyl; R⁹ and R¹⁰ are each—(C₁–C₆)alkyl; R¹¹ is hydrogen or —(C₁–C₆)alkyl; and R¹² is asubstituent selected from the group consisting of hydrogen,—(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl,and —(C₁–C₉)heteroaryl; wherein said —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl, and —(C₁–C₉)heteroaryl R¹²substituent is optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,—CF₃, —CN, —(C₁–C₆)alkyl, —NH(C₁–C₆)alkyl, —NH(C₃–C₇)cycloalkyl,—NH(C₂–C₉)heterocyclyl, —NH(C₆–C₁₀)aryl, —NH(C₁–C₉)heteroaryl,—N((C₁–C₆)alkyl)₂, —N((C₃–C₇)cycloalkyl)₂, —N((C₂–C₉)heterocyclyl)₂,—N((C₆–C₁₀)aryl)₂, —N((C₁–C₉)heteroaryl)₂, —O(C₁–C₆)alkyl,—O(C₃–C₇)cycloalkyl, —O(C₂–C₉)heterocyclyl, —O(C₆–C₁₀)aryl,—O(C₁–C₉)heteroaryl, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —CO₂R⁷,—CONH₂, —CONHR⁷, and —CONR⁷R⁸; wherein R⁷ and R⁸ of said —CONR⁷R⁸ groupmay be taken together with the atoms which they are attached to form a—(C₂–C₉) heterocyclyl.
 2. A compound according to claim 1 wherein Ar is


3. A compound according to claim 2 wherein Ar is a fused ring systemselected from the group consisting of:

with the proviso that Rb of formula III cannot be hydrogen.
 4. Acompound according to claim 1 wherein Ar is


5. A compound according to claim 1 wherein Ar is

with the proviso that Rb is not hydrogen.
 6. A compound according toclaim 1 wherein Ar is


7. A compound according to claim 1 wherein Ar is


8. A compound according to claim 1 wherein Ar is


9. A compound according to claim 1 wherein Ar is a heterocyclic fusedring system selected from:


10. A compound according to claim 1 wherein R³ is hydrogen.
 11. Acompound according to claim 1 wherein R³ is selected from the groupconsisting of —(C₆–C₁₀)aryl and —(C₁–C₉)heteroaryl, optionallysubstituted by one to three moieties independently selected from thegroup consisting of halogen, hydroxy, —(C₁–C₆)alkyl,—(C₁–C₆)alkyl-P(O)(O(C₁–C₆)alkyl)₂, —(C₃–C₁₀)cycloalkyl, (C₆–C₁₀)aryl,(C₂–C₉)heterocyclyl, —(C₁–C₉)heteroaryl, —NR⁵R⁶, —NHSO₂(C₁–C₆)alkyl,—NHSO₂(C₃–C₆)cycloalkyl, —N((C₁–C₆)alkyl)(SO₂—C₁–C₆)alkyl),—N((C₁–C₆)alkyl)(SO₂(C₃–C₆)cycloalkyl),—N((C₃–C₆)cycloalkyl)(SO₂—C₁–C₆)alkyl),—N((C₃–C₆)cycloalkyl)(SO₂(C₃–C₆)cycloalkyl), —O(C₁–C₆)alkyl,—O—SO₂(C₁–C₆)alkyl, —O—SO₂(C₃–C₆)cycloalkyl, —(CO)(C₁–C₆)alkyl,—(CO)CF₃, —(CO)(C₃–C₁₀)cycloalkyl, —(CO)(C₆–C₁₀)aryl,—(CO)(C₂–C₉)heterocyclyl, —(CO)(C₁–C₉)heteroaryl, —(CO)O(C₁–C₆)alkyl,—(CO)O(C₃–C₁₀)cycloalkyl, —(CO)O(C₆–C₁₀)aryl, —(CO)O(C₂–C₉)heterocyclyl,—(CO)O(C₁–C₉)heteroaryl, —(CO)(C₁–C₆)alkyl-O(C₁–C₆)alkyl,—SO₂(C₁–C₆)alkyl, —SO₂(C₃–C₆)cycloalkyl, SO₂CF₃, SO₂NH₂,SO₂NH(C₁–C₆)alkyl, —SO₂NH(C₃–C₆)cycloalkyl, —SO₂N((C₁–C₆)alkyl)₂,SO₂N((C₁–C₆)alkyl)((C₃–C₆)cycloalkyl), —SO₂N((C₃–C₆)cycloalkyl)₂ and—SO₂NR⁵R⁶, wherein said —(C₁–C₁₀) aryl or —(C₁–C₉) heteroaryl areoptionally interrupted by one to three elements selected from the groupconsisting of —S—, —O—, —N—, —NH— and —NR¹².
 12. A compound according toclaim 1 wherein R³ is selected from the group consisting of—(C₃–C₁₀)cycloalkyl, —(C₂–C₉)heterocyclyl, and —(C₁–C₆)alkyl-(C₂–C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of halogen, hydroxy,—(C₁–C₆)alkyl, —(C₁–C₆)alkyl-P(O)(O(C₁–C₆)alkyl)₂, —(C₃–C₁₀)cycloalkyl,(C₆–C₁₀)aryl, (C₂–C₉)heterocyclyl, —(C₁–C₉)heteroaryl, —NR⁵R⁶,—NSO₂(C₁–C₆)alkyl, —NHSO₂(C₃–C₆)cycloalkyl,—N((C₁–C₆)alkyl)(SO₂—C₁–C₆)alkyl),—N((C₁–C₆)alkyl)(SO₂(C₃–C₆)cycloalkyl),—N((C₃–C₆)cycloalkyl)(SO₂—C₁–C₆)alkyl),—N((C₃–C₆)cycloalkyl)(SO₂(C₃–C₆)cycloalkyl), —O(C₁–C₆)alkyl,—O—SO₂(C₁–C₆)alkyl, —O—SO₂(C₁–C₆)alkyl, —O—SO₂(C₃–C₆)cycloalkyl,—(CO)(C₁–C₆)alkyl, —(CO)CF₃, —(CO)(C₃–C₁₀)cycloalkyl, —(CO)(C₆–C₁₀)aryl,—(CO)(C₂–C₉)heterocyclyl, —(CO)(C₁–C₉)heteroaryl, —(CO)O(C₁–C₆)alkyl,—(CO)O(C₃–C₁₀)cycloalkyl, —(CO)O(C₆–C₁₀)aryl, —(CO)O(C₂–C₉)heterocyclyl,—(CO)O(C₁–C₉)heteroaryl, —(CO)(C₁–C₆)alkyl-O(C₁–C₆)alkyl,—SO₂(C₁–C₆)alkyl, —SO₂(C₃–C₆)cycloalkyl, SO₂CF₃, SO₂NH₂,SO₂NH(C₁–C₆)alkyl, —SO₂NH(C₃–C₆)cycloalkyl, —SO₂N((C₁–C₆)alkyl)₂,SO₂N((C₁–C₆)alkyl)((C₃–C₆)cycloalkyl), —SO₂N((C₃–C₆)cycloalkyl)₂ and—SO₂NR⁵R⁶, wherein said —(C₃–C₁₀)cycloalkyl, —(C₂–C₉)heterocyclyl, and—(C₁–C₆)alkyl-(C₂–C₉) heterocyclyl are optionally interrupted by one tothree elements selected from the group consisting of —(C═O), —SO₂, —S—,—O—, —N—, —NH— and —NR¹².
 13. A compound according to claim 1 wherein R³is —(C₁–C₆)alkyl optionally substituted by one to three moietiesselected from the group consisting of halogen, hydroxy, —(C₁–C₆)alkyl,—(C₁–C₆)alkyl-P(O)(O(C₁–C₆)alkyl)₂, —(C₃–C₁₀)cycloalkyl, (C₆–C₁₀)aryl,(C₂–C₉)heterocyclyl, —(C₁–C₉)heteroaryl, —NR⁵R⁶, —NHSO₂(C₁–C₆)alkyl,—NHSO₂(C₃–C₆)cycloalkyl, —N((C₁–C₆)alkyl)(SO₂—C₁–C₆)alkyl),—N((C₁–C₆)alkyl)(SO₂(C₃–C₆)cycloalkyl),—N((C₃–C₆)cycloalkyl)(SO₂—C₁–C₆)alkyl),—N((C₃–C₆)cycloalkyl)(SO₂(C₃–C₆)cycloalkyl), —O(C₁–C₆)alkyl,—O—SO₂(C₁–C₆)alkyl, —O—SO₂(C₃–C₆)cycloalkyl, —(CO)(C₁–C₆)alkyl,—(CO)CF₃, —(CO)(C₃–C₁₀)cycloalkyl, —(CO)(C₆–C₁₀)aryl,—(CO)(C₂–C₉)heterocyclyl, —(CO)(C₁–C₉)heteroaryl, —(CO)O(C₁–C₆)alkyl,—(CO)O(C₃–C₁₀)cycloalkyl, —(CO)O(C₆–C₁₀)aryl, —(CO)O(C₂–C₉)heterocyclyl,—(CO)O(C₁–C₉)heteroaryl, —(CO)(C₁–C₆)alkyl-O(C₁–C₆)alkyl,—SO₂(C₁–C₆)alkyl, —SO₂(C₃–C₆)cycloalkyl, SO₂CF₃, SO₂NH₂,SO₂NH(C₁–C₆)alkyl, —SO₂NH(C₃–C₆)cycloalkyl, —SO₂N((C₁–C₆)alkyl)₂,SO₂N((C₁–C₆)alkyl)((C₃–C₆)cycloalkyl), —SO₂N((C₃–C₆)cycloalkyl)₂ and—SO₂NR⁵R⁶, wherein said —(C₁–C₆)alkyl is optionally interrupted by oneto three elements selected from the group consisting of —(C═O), —SO₂,—S—, —O—, —N—, —NH— and —NR¹².
 14. A compound according to claim 1wherein Ra is selected from the group consisting of hydrogen, halogen,hydroxy, —CF₃ and —CN.
 15. A compound according to claim 1 wherein Rb isselected from the group consisting of hydrogen, —(C₁–C₆)alkyl,—(C₃–C₇)cycloalkyl and —(C₂–C₉)heterocyclyl.
 16. A compound according toclaim 1 wherein each Rc independently represents a substituent selectedfrom the group consisting of hydrogen, hydroxy, —(C₁–C₆)alkyl,—(C₃–C₇)cycloalkyl, and —(C₂–C₉)heterocyclyl, or two Rc substituents maybe taken together with the atom(s) to which they are attached to form acyclic group, —(C₃–C₁₀)-cycloalkyl or —(C₂–C₉)—heterocyclyl.
 17. Acompound selected from the group consisting of:N-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-methanesulfonamideN-Methyl-N-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideEthanesulfonic acidmethyl-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amideN-(3-Methanesulfonylamino-5-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Ethyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-Methyl-N-(4-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-(5,6-Dimethyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-N-methyl-methanesulfonamideEthanesulfonic acidmethyl-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-amideN-Ethyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideEthanesulfonic acidethyl-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amide4-{4-[2-(1-Methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-oneN-Ethyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamideN-(2-{[2-(2-Oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide4-{4-[((R)-1-Methanesulfonyl-pyrrolidin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-oneN-Methyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Methyl-N-(2-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Methyl-N-{3-[({methyl-[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-amino})-methyl]-phenyl}-methanesulfonamideN-Methyl-N-(3-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Methyl-N-{4-methyl-3-[({methyl-[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-amino})-methyl]-phenyl}-methanesulfonamideN-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-(5-Methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-(3-Fluoro-2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamideEthanesulfonic acidethyl-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amide4-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one4-{4-[2-((S)-1-Methanesulfonyl-pyrrolidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-oneN-Ethyl-N-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide4-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-oneN-(2-Fluoro-6-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamideEthanesulfonic acidmethyl-(3-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amideN-(4-Fluoro-2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamideN-Cyclopropyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Methyl-N-(4-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-Methyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamideN-{2,2-Dimethyl-3-[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-N-methyl-methanesulfonamideN-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-4-yl)-methanesulfonamideN-(2,4-Difluoro-6-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamideN-Cyclopropyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide3-{[2-(2-Oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-benzenesulfonamide4-{4-[(1-Methanesulfonyl-piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-oneN-(3-{[2-(2-Oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Methyl-N-{2-[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-methanesulfonamideN-Methyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-4-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide.18. A compound selected from the group consisting of:N-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-methanesulfonamideEthanesulfonic acidmethyl-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amideN-(3-Methanesulfonylamino-5-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Ethyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-(5,6-Dimethyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-N-methyl-methanesulfonamideEthanesulfonic acidmethyl-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-amideN-Ethyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideEthanesulfonic acidethyl-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amide6-{4-[2-(1-Methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-oneN-Ethyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamideN-(2-{[2-(2-Oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide6-{4-[((R)-1-Methanesulfonyl-pyrrolidin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-oneN-Methyl-N-{3-[({methyl-[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-amino})-methyl]-phenyl}-methanesulfonamideN-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideEthanesulfonic acidethyl-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amideN-Ethyl-N-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-(2-Fluoro-6-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamideEthanesulfonic acidmethyl-(3-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amideN-Cyclopropyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Methyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamideN-{2,2-Dimethyl-3-[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-N-methyl-methanesulfonamideN-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-4-yl)-methanesulfonamideN-(2,4-Difluoro-6-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamideN-Cyclopropyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide3-{[2-(2-Oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-benzenesulfonamide6-{4-[(1-Methanesulfonyl-piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-oneN-(3-{[2-(2-Oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Methyl-N-{2-[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-methanesulfonamideN-Methyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide6-{4-[2-(1-Methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one6-{4-[(4-Methanesulfonyl-pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-oneN-(4-Methoxy-3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-{2,2-Dimethyl-3-[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamideN-(4-Methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideEthanesulfonic acidmethyl-{3-[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-amideN-(4-Fluoro-3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide6-[4-(3-Methanesulfonylmethyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-onePropane-1-sulfonic acidmethyl-{3-[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-amideN-Methyl-N-(4-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide6-{4-[(6-Methanesulfonyl-pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one6-{4-[(5-Cyclopropyl-1H-pyrazol-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one6-{4-[(5-Methanesulfonyl-pyridin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-oneN-(3-Methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Methyl-N-(6-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-Isopropyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamideN-(4-Methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-(2-Methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide6-[4-(2-Methanesulfonylmethyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-oneN-Methyl-N-(3-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-Methyl-N-(5-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-Methyl-N-(4-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-Methyl-N-(2-methyl-5-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamideN-Methyl-N-(5-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-Methyl-N-(6-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamideN-Methyl-N-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamideN-Methyl-N-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamide.19. A compound selected from the group consisting of:N-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-methanesulfonamideN-Methyl-N-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideEthanesulfonic acidmethyl-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amideN-(3-Methanesulfonylamino-5-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Ethyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-Methyl-N-(4-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-(5,6-Dimethyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-N-methyl-methanesulfonamideEthanesulfonic acidmethyl-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-amideN-Ethyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideEthanesulfonic acidethyl-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amide7-{4-[2-(1-Methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-oneN-Ethyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamideN-(2-{[2-(2-Oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide7-{4-[((R)-1-Methanesulfonyl-pyrrolidin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-oneN-Methyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Methyl-N-(2-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Methyl-N-{3-[({methyl-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-amino})-methyl]-phenyl}-methanesulfonamideN-Methyl-N-(3-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Methyl-N-{4-methyl-3-[({methyl-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-amino})-methyl]-phenyl}-methanesulfonamideN-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-(5-Methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-(3-Fluoro-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamideEthanesulfonic acidethyl-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amide7-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one7-{4-[2-((S)-1-Methanesulfonyl-pyrrolidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-oneN-Ethyl-N-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide7-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-oneN-(2-Fluoro-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamideEthanesulfonic acidmethyl-(3-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-amideN-(4-Fluoro-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamideN-Cyclopropyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Methyl-N-(4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-Methyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamideN-{2,2-Dimethyl-3-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-N-methyl-methanesulfonamideN-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-4-yl)-methanesulfonamideN-(2,4-Difluoro-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamideN-Cyclopropyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide3-{[2-(2-Oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-benzenesulfonamide7-{4-[(1-Methanesulfonyl-piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-oneN-(3-{[2-(2-Oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Methyl-N-{2-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-methanesulfonamideN-Methyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamideMethanesulfonic acid3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenylester7-{4-[2-(1-Methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-oneN-(4-Fluoro-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide7-{4-[(4-Methanesulfonyl-pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-oneN-(4-Methoxy-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-{2,2-Dimethyl-3-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamideN-(4-Methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideEthanesulfonic acidmethyl-{3-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-amideN-(4-Fluoro-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide7-[4-(3-Methanesulfonylmethyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-onePropane-1-sulfonic acidmethyl-{3-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-amide7-{4-[((S)-1-Methanesulfonyl-piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-oneN-Methyl-N-(4-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide7-{4-[(6-Methanesulfonyl-pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one7-{4-[(5-Cyclopropyl-1H-pyrazol-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one7-{4-[(5-Methanesulfonyl-pyridin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-oneN-(3-Methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Methyl-N-(6-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-Isopropyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamideN-(4-Methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-(4,6-Dimethyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-N-methyl-methanesulfonamideN-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-(2-Methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide7-[4-(2-Methanesulfonylmethyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-oneN-Methyl-N-(3-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-Methyl-N-(5-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-Methyl-N-(4-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-Methyl-N-(2-methyl-5-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamideN-Methyl-N-(5-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-Methyl-N-(6-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamideN-Methyl-N-(5-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamideN-Methyl-N-(5-methyl-2-{([2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamideN-Methyl-N-(4-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamideN-Methyl-N-(3-methyl-4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-Methyl-N-(5-methyl-4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-2-yl)-methanesulfonamideN-Methyl-N-(6-methyl-5-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamideN-Methyl-N-(6-methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamideN-Methyl-N-(5-methyl-4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-Methyl-N-(2-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-4-yl)-methanesulfonamideN-Methyl-N-(6-methyl-4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-Methyl-N-(5-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-4-yl)-methanesulfonamideN-Methyl-N-(5-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamideN-Methyl-N-(5-methyl-4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamideN-Methyl-N-(6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamideN-Methyl-N-(6-methyl-4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-2-yl)-methanesulfonamideN-Methyl-N-(2-methyl-4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamideN-Methyl-N-(5-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamideN-Methyl-N-(2-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamideN-Methyl-N-(6-methyl-4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamideN-Methyl-N-(4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-5-yl)-methanesulfonamideN-Methyl-N-(2-methyl-5-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamideN-Methyl-N-(4-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-5-yl)-methanesulfonamideN-Methyl-N-(5-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-methanesulfonamideN-Methyl-N-(5-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-methanesulfonamideN-Methyl-N-(2-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-5-yl)-methanesulfonamideN-Methyl-N-(3-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-methanesulfonamideN-Methyl-N-(6-methyl-5-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamideN-Methyl-N-(6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-Methyl-N-(4-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamideN-Methyl-N-(5-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamideN-Methyl-N-(4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-3-yl)-methanesulfonamideN-Methyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-4-yl)-methanesulfonamideN-Methyl-N-(4-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrimidin-2-yl)-methanesulfonamideN-Methyl-N-(6-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-methanesulfonamideN-Methyl-N-(6-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyrazin-2-yl)-methanesulfonamide.